Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients.

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.

Second report of RING finger protein 113A (RNF113A) involvement in a Mendelian disorder.

RING Finger Protein 113 A (RNF113A, MIM 300951) is a highly conserved gene located on chromosome Xq24-q25, encoding a protein containing two conserved zinc finger domains involved in DNA alkylation repair and premessenger RNA splicing. To date, only one pathogenic variant of RNF113A, namely c.901C>T; p.Gln301Ter, has been reported in humans by Tarpey et al. in 2009. Thereafter, Corbett et al. stated that this variant was responsible for an X-linked form of nonphotosensitive trichothiodystrophy associated with profound intellectual disability, microcephaly, partial corpus callosum agenesis, microphallus, and absent or rudimentary testes. This variant was then shown to alter DNA alkylation repair, providing an additional argument supporting its pathogenicity and important clues about the underlying pathophysiology of nonphotosensitive trichothiodystrophy. Using exome sequencing, we identified exactly the same RNF113A variant in two fetuses affected with abnormalities similar to those previously reported by Corbett et al. To our knowledge, this is the second report of a RNF113A pathogenic variant in humans.

The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance.

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.

Prenatal diagnosis of focal dermal hypoplasia: Report of three fetuses and review of the literature.

Focal dermal hypoplasia (FDH) is a rare syndrome characterized by pleiotropic features knowing to involve mostly skin and limbs. Although FDH has been described in children and adults, the cardinal signs of the fetal phenotype are not straightforward impacting the quality of the prenatal diagnosis. We describe in depth the ultrasound, radiological, macroscopical, and histological phenotype of three female fetuses with a severe form of FDH, propose a review of the literature and an attempt to delineate minimal and cardinal signs for FDH diagnosis. This report confirms the variability of FDH phenotype, highlights unreported FDH features, and allows delineating evocative clinical associations for prenatal diagnosis, namely intrauterine growth retardation, limbs malformations, anterior wall/diaphragm defects, and eye anomalies. © 2016 Wiley Periodicals, Inc.

Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis.

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.

Prenatal diagnosis of CHARGE syndrome by identification of a novel CHD7 mutation in a previously unaffected family.

CHARGE syndrome comprises ocular coloboma (C), heart malformation (H), choanal atresia (A), retardation of growth and/or anomalies of the central nervous system (R), genital anomalies (G) and ear anomalies (E). Prenatal diagnosis of CHARGE syndrome may be suspected in the presence of specific major anomalies at ultrasound examination. We describe prenatal diagnosis of CHARGE syndrome confirmed by identification of a mutation in CHD7 gene in a previously unaffected family.

Fatal Myopericarditis Following an Influenza A (H3N2) Infection.

BACKGROUND Influenza viruses induce uncomplicated infections in most cases in individuals with no known predisposing factors. Acute febrile illness is generally limited to upper respiratory symptoms and several constitutional symptoms, including headache, lethargy, and myalgia. However, influenza A virus is a cause of severe morbidity and mortality worldwide. Some patients are at risk for serious and fatal complications. Cardiac involvement is a well-known condition, but, clinically apparent influenza myocarditis is not common. Few reports exist regarding recurrent fulminant influenza myocarditis. CASE REPORT We report here a fatal case of heart failure following myocarditis in a 14-year-old female who had seasonal flu symptoms but was otherwise healthy. H3N2 influenza virus infection was detected by molecular analyses of throat and nasal swabs, suggesting damage to myocardial cells caused directly by the virus. CONCLUSIONS Pericardial effusion myopericarditis may occur during influenza virus infection in young individuals, even those with no known predisposing factors. Physicians need to be aware that acute myopericarditis can be a fatal complication of recent influenza virus infection in all patients with instable hemodynamics. Early diagnosis and treatment could reduce, in some cases, the risk of severe cardiac events. However, this sudden and fatal outcome was difficult to predict in a healthy young female with no known risk factors.

Phenol sulfotransferase SULT1A1*2 allele and enhanced risk of upper urinary tract urothelial cell carcinoma.

Cytosolic sulfotransferases (SULT) are involved in detoxification pathways. A functional polymorphism in the SULT1A1 gene, leading to an Arg213His substitution (SULT1A1*2), is thought to confer susceptibility to various types of cancer. Upper urinary tract urothelial cell carcinomas (UUT-UCC) are rare (5% of all urothelial carcinomas). We genotyped 268 patients with UUT-UCC and 268 healthy controls matched for age, gender, tobacco consumption, and ethnicity. His213 (SULT1A1*2) allele frequency was significantly higher in patients than in controls (37.1% versus 28.9%; P=0.004). The His/His genotype corresponding to low-activity SULT1A1 enzyme conferred a significantly higher risk of UUT-UCC (odds ratio, 2.18; 95% confidence interval, 1.28-3.69; P=0.004

Usefulness of repeated fine-needle cytology in the follow-up of non-operated thyroid nodules.

OBJECTIVE: The usefulness of repeated fine-needle cytology (FNC) in thyroid nodules with benign cytology remains unknown. We analyzed the relevance of repeated FNC to detect suspicious or malignant (S/M) cytologies and carcinomas. DESIGN: A retrospective study (1983-2004) was conducted in our endocrinology department. METHODS: We reviewed the reports of 895 adequate FNC performed in 298 patients (298 nodules) during a mean follow-up of 5 years. We compared the nodules with at least one suspicious or malignant FNC (S/M nodules) with nodules with repeatedly benign (RB) FNC (RB nodules). RESULTS: Among the nodules with initial benign cytology, we found 35 nodules with one or more later suspicious or malignant results. The interval between the first FNC and the first S/M FNC was 2.9 years. The probability for a nodule to have a repeated benign FNC decreases with time and with the number of FNC. We did not find any clinical or ultrasonographic characteristics related to an S/M cytology. Seven cancers were detected by the second or the third FNC with S/M results. The proportion of cancers among S/M nodules was similar when S/M cytology appears during the first, the second, or the third FNC. CONCLUSIONS: We suggest to repeat FNC up to three adequate samples in the follow-up of thyroid nodules so as not to miss the presence of malignant neoplasm.

Duodenopancreatectomy for cystic dystrophy in heterotopic pancreas of the duodenal wall.

AIM OF THE STUDY: Cystic dystrophy in heterotopic pancreas (CDHP) is rare. The aim of this study was to evaluate the diagnosis, management, and follow-up of the CDHP. PATIENTS AND METHODS: Between August 1990 and March 2004, 12 patients with CDHP underwent a duodenopancreatectomy. The patients were retrospectively reviewed. RESULTS: There were 11 men and 1 woman with a mean age of 42.4 years (range: 34-54 years). Nine patients (75%) were alcoholic and 8 patients had chronic pancreatitis. The diagnosis of CDHP was performed in 8 patients (66.6%) after the preoperative workup. Seven patient had a medical treatment with octreotid and endoscopic cystic ponction (N=3) or cystic fenestration (N=1). Recurrence of pain was noted after a mean period of 5 months. Three patients had recurrent acute pancreatitis. Duodenopancreatectomy was performed in all cases. The mortality and morbidity rate were respectively 8.3% (N=1) and 25% (N=3). Mean follow-up was 64 months (ranges: 6 - 158 months). One patient was seen 70 months later with epigastric pain and features of acute pancreatitis of the pancreatic stump due to anastomotic stenosis. The other patients were asymptomatic. CONCLUSIONS: Diagnosis of CDHP is difficult. After failure of medical treatment, duodenopancreatectomy can be proposed.

Histopathology of prostate tissue after vascular-targeted photodynamic therapy for localized prostate cancer.

Low-risk prostate adenocarcinoma is classically managed either with active surveillance or radical therapy (such as external radiotherapy or radical prostatectomy), but both have significant side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy proposed as an alternative approach for localized, low-volume, and low-Gleason score (≤6) carcinomas. We report histological modifications observed in prostate biopsies of 56 patients, performed 6 months after VTP using the photosensitizer TOOKAD® Soluble (WST11) and low-energy laser administered in the tumor area transperineally by optic fibers. In 53 patients, we observed sharply demarcated hyaline fibrotic scars, with or without rare atrophic glands, sometimes reduced to corpora amylacea surrounded by giant multinuclear macrophages. Mild chronic inflammation, hemosiderin, and coagulative necrosis were also observed. When residual cancer was present in a treated lobe (17 patients), it was always located outside the scar, most often close to the prostate capsule, and it showed no therapy-related modification. Histopathological interpretation of post-WST11 VTP prostate biopsies was straightforward, in contrast with that of prostate biopsies after radio or hormonal therapy, which introduces lesions difficult to interpret. VTP resulted in complete ablation of cancer in the targeted area.

An elevated level of TSH might be predictive of differentiated thyroid cancer.

Suppression therapy of thyreostimulin (TSH) using thyroid hormones improves survival of subjects operated for differentiated thyroid cancer. The TSH level might be different depending on the type of nodule. The objective of this study was to compare retrospectively the TSH level between two groups of subjects who underwent total thyroidectomy for a nodule, matched on sex, ethnicity, age and biological method of TSH measurement, one whose final histology was benign and one malignant. There was no significant difference between the two groups in terms of age, sex, family history of thyroid disease or thyroid autoimmunity. The subjects, whose final histology was malignant, had a mean TSH level significantly higher than subjects with benign disease (1.55 mU/l versus 0.96 mU/l, P=0.003). Cancer risk was greater when the TSH was in the upper tertile of normal range. There was no correlation between the risk of thyroid cancer and age, sex, family history of thyroid disease, or menopausal status. The relative risk of having thyroid carcinoma was higher when the margins of nodules were blurred or in the presence of microcalcifications. These data confirm a trend toward baseline values of TSH higher in subjects with a thyroid-differentiated cancer. However, we could not define a preoperative threshold that would reliably determine the malignant or benign nature of the nodule.

Increasing the number of thyroid lesions classes in microarray analysis improves the relevance of diagnostic markers.

BACKGROUND: Genetic markers for thyroid cancers identified by microarray analysis have offered limited predictive accuracy so far because of the few classes of thyroid lesions usually taken into account. To improve diagnostic relevance, we have simultaneously analyzed microarray data from six public datasets covering a total of 347 thyroid tissue samples representing 12 histological classes of follicular lesions and normal thyroid tissue. Our own dataset, containing about half the thyroid tissue samples, included all categories of thyroid lesions. METHODOLOGY/PRINCIPAL FINDINGS: Classifier predictions were strongly affected by similarities between classes and by the number of classes in the training sets. In each dataset, sample prediction was improved by separating the samples into three groups according to class similarities. The cross-validation of differential genes revealed four clusters with functional enrichments. The analysis of six of these genes (APOD, APOE, CLGN, CRABP1, SDHA and TIMP1) in 49 new samples showed consistent gene and protein profiles with the class similarities observed. Focusing on four subclasses of follicular tumor, we explored the diagnostic potential of 12 selected markers (CASP10, CDH16, CLGN, CRABP1, HMGB2, ALPL2, ADAMTS2, CABIN1, ALDH1A3, USP13, NR2F2, KRTHB5) by real-time quantitative RT-PCR on 32 other new samples. The gene expression profiles of follicular tumors were examined with reference to the mutational status of the Pax8-PPARgamma, TSHR, GNAS and NRAS genes. CONCLUSION/SIGNIFICANCE: We show that diagnostic tools defined on the basis of microarray data are more relevant when a large number of samples and tissue classes are used. Taking into account the relationships between the thyroid tumor pathologies, together with the main biological functions and pathways involved, improved the diagnostic accuracy of the samples. Our approach was particularly relevant for the classification of microfollicular adenomas.

Prenatal diagnosis of primary anophthalmia with a 3q27 interstitial deletion involving SOX2.

We report an interstitial deletion of chromosome 3q26-q28 in a fetus in which anophthalmia had been detected prenatally. FISH analysis, using BAC clones encompassing the SOX2 locus, showed that SOX2 gene was involved in the chromosomal breakpoint of the deletion. This case confirms that haploinsufficiency for SOX2 plays a crucial role in human eye development and emphasizes the necessity of careful chromosomal analysis, including FISH analysis of the 3q region, in case of prenatal discovery of anophthalmia.