Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Diagnosis of congenital abnormalities with post-mortem ultrasound in perinatal death.

PURPOSE: To determine the sensitivity and specificity of post-mortem ultrasound in the diagnosis of major congenital abnormalities of fetuses using conventional autopsy as the standard of reference. MATERIAL AND METHODS: All fetuses coming from terminations of pregnancy or intrauterine fetal deaths in a single institution were included. A total of 75 fetuses were included during the study period. The results of post-mortem ultrasound examinations were compared to those of conventional autopsy that served as standard of reference. RESULTS: Gestational age of the fetuses ranged from 15 to 38 weeks gestation. A complete post-mortem ultrasound assessment was possible in all fetuses. Regarding detection of brain abnormalities, post-mortem ultrasound had a sensitivity of 81.5% or 4/5 (95% CI: 63.3-91.8%), and a specificity of 97.9% (95% CI: 89.1-99.6%). Specificities for the diagnosis of thoracic, cardiac, urinary tract, spinal and bone abnormalities were 100%. CONCLUSION: Post-mortem ultrasound shows high sensitivity and specificity for the diagnosis of congenital structural abnormalities as compared to conventional autopsy, with the exception of congenital cardiac diseases.

[Neonatal presentation of Prader-Willi syndrome: A report of five cases]. / Présentation néonatale du syndrome de Prader-Willi : à propos de 5 cas.

Prader-Willi syndrome (PWS) is a fingerprint disease caused by the loss of paternally inherited chromosome 15q11.2-q13. In several populations studied, prevalence is estimated to be from 1/10,000 to 1/25,000 births. The disease initially manifests by neonatal hypotonia associated with orality disorders. Secondly, hyperphagia appears with significant obesity and hypogonadism. Motor milestones and language development are delayed, and all individuals have variable degrees of cognitive disability during childhood. Frequently, the most prominent features do not become evident until the later childhood stage, which can lead to underdiagnosis or late diagnosis in early childhood. Because of the long-term implications of this syndrome, it is important to recognize its features as soon as possible so that early counseling of parents and the affected child is possible. The diagnosis is suspected on clinical grounds and confirmed by genetic analysis. Prenatal diagnosis is possible and can be considered in polyhydramnios, decreased fetal active movements, malpresentation, oddly positioned hands and feet, and abnormal fetal heart rhythm. Since PWS can also lead to complications in both pregnancy and labor, proper prenatal diagnosis can also help optimize perinatal care for affected children. We report a series of five newborns for whom PWS was diagnosed in the neonatal period over 6 years. During this period, no prenatal signs of PWS were detected. The incidence in our population was 1/7937 births. The disease was diagnosed on clinical criteria: severe hypotonia, failure to thrive with poor sucking, and dysmorphic and abnormalities of the genitalia. Polyhydramnios was observed in only one case. The delivery was normal for only one patient. All except one were term newborns. There were three males and two females. We noted abnormal fetal heart rate for 80 % of the patients. The birth weight was close to the 10th percentile for two patients, less than the 3rd percentile for two others. All individuals had eutrophic cranial perimeter and four presented peculiar position of fingers. Genetic analyses found a deletion of the paternal chromosome 15 in three patients (60 %) and maternal uniparental disomy for the two others (40 %). The distribution by sex, weight, cranial perimeter, and mutations are those reported in the literature. PWS should be sought in cases of severe neonatal hypotonia, most particularly if it combines dysmorphism, hypogonadism, malposition of the fingers, and suggestive prenatal history. An early diagnosis provides better multidisciplinary care for the patient and family. We have no explanation for the higher incidence of the disease than in the general population. It is possible that this incidence is only fortuitous, but further studies would help to identify potential risk factors for the disease.

[How to deal with a fetal head circumference lower than the third percentile?] / Gestion prénatale des fœtus avec un périmètre crânien inférieur au 3e percentile.

The prenatal finding of a head circumference (HC) below the 3rd percentile (p) remains, in the same way as short femur or increased nuchal translucency with normal karyotype, one the most difficult situations for the praticionner in the setting of prenatal diagnosis. Microcephaly is a gateway to possible cerebral pathologies, but the main objective is to identify serious prenatal situations. A standardized HC measurement, the use of adapted reference tools and charts, longitudinal following of cephalic biometrics in high-risk situations, and systematic central nervous system analysis can increase the diagnostic performance of ultrasound which is often disappointing for microcephaly. The early distinction between associated or isolated microcephaly makes it possible to quickly orient the prenatal management and counseling. Fetal MRI and genetic counseling are fundamental in this context, making it possible to specify at best the etiological diagnosis and to provide assistance to the neuropediatrician in the establishment of an often uncertain prognosis. The recent increase in cases of microcephaly concomitant with the epidemic of the ZIKA virus is an additional argument to improve our practices and the daily apprehension of HC<3rd p.

[Segmental approach to congenital heart diseases: Principles and applications to prenatal imaging]. / Approche segmentaire des cardiopathies congénitales : principes et applications en imagerie prénatale.

This pictorial essay will initially present the origin, definitions, objectives and main principles of the segmental approach to congenital heart diseases. Then, through ultrasound scans iconography we will consider its practical applications to prenatal screening. Eventually, through both ultrasound and MRI cases, we will discuss its potential use in fetal diagnostic evaluation.

Added value of MRI for the prenatal diagnosis of isolated orofacial clefts and comparison with ultrasound.

OBJECTIVES: To evaluate the added value of fetal magnetic resonance imaging (MRI) in diagnosing and assessing isolated orofacial clefts and compare MRI with second-line diagnostic ultrasound. MATERIALS AND METHODS: In a two-year prospective bicenter study, fetuses with isolated orofacial clefts were reassessed using second-line diagnostic ultrasound and MRI. The results of second line ultrasound and those MRI were compared to each other. The gestational age at the time of ultrasound and MRI, and the final diagnosis for each of the imaging modalities were recorded. Finally, the results of second line ultrasound and those of MRI were compared to the results of neonatal clinical examination after delivery that served as standard of reference. RESULTS: Twenty-two women were included after informed consent was obtained. On average, diagnostic ultrasound was performed at 25.5weeks of gestation (range: 24-34weeks) and MRI at 29.5weeks of gestation (range: 27-34weeks). The results of ultrasound and those of MRI findings were strictly consistent in 20 women (20/22; 91%) but differed in 2 women (2/22; 9%). For all fetuses, the final radiological diagnosis was confirmed by clinical examination after delivery. CONCLUSION: If ultrasound examination proves technically challenging, fetal MRI can be used to obtain the same diagnostic information in 91% of cases and can help surgeons and interdisciplinary teams provide appropriate antenatal counseling.

Prenatal diagnosis of bowel malposition using T2-weighted fetal MRI sequences.

OBJECTIVE: The goal of this study was to investigate the capability of T2-weighted magnetic resonance imaging (MRI) in revealing fetal bowel malposition. MATERIALS AND METHODS: All fetal MRI examinations (excluding central nervous system MRI examinations) performed in our department from January 2005 to January 2014 were retrospectively studied by 2 independent observers for situs, stomach and jejunum location on T2-weighted images. Patients data were also reviewed for results of ultrasound examinations, MRI indication, and gestational age. Abnormally positioned jejunums were classified into 3 groups: intrathoracic (A), extra-fetal (B) and abnormal intra-fetal (C). Prenatal data were compared to postnatal imaging, surgery or autopsy findings that served as standard of reference. RESULTS: A total of 709 fetal MRI examinations were analyzed. In 64 fetus (9%), the jejunum was not present in the left subgastric area on T2-weighted MR images. In these 64 fetuses, proximal jejunum was intrathoracic (41/64, 64%, group A), extra-fetal (11/64, 17%, group B), or intra-abdominal but abnormally positioned (12/64, 19%, group C). Interobserver agreement was 100%. All diagnoses for fetuses in groups A and B (52 cases) were confirmed postnatally (41 cases) or at autopsy (11 cases). In group C, bowel malposition was suspected after ultrasound in only 2/12 fetuses (16.6%); it was confirmed postnatally in 1 fetus but not confirmed in the remaining one. In the 10 remaining fetuses (83%), malposition was confirmed postnatally although not initially suspected. CONCLUSION: T2-weighted fetal MR images are useful for the prenatal diagnosis of bowel malposition, even when they are unsuspected on ultrasound examination.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

[Post-mortem perinatal imaging: State of the art and perspectives, with an emphasis on ultrasound]. / Imagerie post-mortem périnatale : état des lieux, point de vue et perspectives, échographiques en particulier.

The fields of application of post-mortem imaging have been exponentially growing for 10 years. Its potential to identify the cause of death in trauma and ballistic cases is now properly documented. In pediatric and perinatal practice, large significant series are less available, except for MRI and central nervous system analysis where scientific evidence is now robust. After a short historical and state-of-the-art review, we will try to depict the way we see the future of this sub-specialty of post-mortem imaging, especially in specific perinatal situations.

Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome.

BACKGROUND: PTEN gene (MIM 601628) is a tumor suppressor gene implicated in PTEN hamartoma tumor syndromes (PHTS) including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndrome. Bannayan-Riley-Ruvalcaba syndrome is considered as the pediatric form of PHTS. More recently, children presenting autism spectrum disorders with macrocephaly (ASD-M) have been reported. METHODS: We report clinical data from seven patients diagnosed in childhood with a PTEN germline mutation, excluding cases of familial Cowden syndrome. RESULTS: This study underlines the variability of phenotype associated with PTEN mutations diagnosed at pediatric age. Most of the patients did not fulfill usual criteria of Bannayan-Riley-Ruvalcaba syndrome or ASD-M. CONCLUSION: PTEN testing should be considered in any child presenting with severe macrocephaly (>+4SD) and another feature of PHTS.

Incidental findings on array comparative genomic hybridization: detection of carrier females of dystrophinopathy without any family history.

Array comparative genomic hybridization (aCGH) has progressively replaced conventional karyotype in the diagnostic strategy of intellectual disability (ID) and congenital malformations. This technique increases not only the diagnostic rate but also the possibility of finding unexpected variants unrelated to the indication of referral, namely incidental findings. The incidental finding of copy number variants (CNVs) located in X-linked genes in girls addresses the crucial question of genetic counseling in the family. We report here five cases of CNVs involving the dystrophin gene detected by aCGH in girls referred for developmental delay, without any family history of dystrophinopathy. The rearrangements included three in-frame deletions; one maternally and two paternally inherited, and two frameshift duplications: one de novo and one from undetermined inheritance. In two cases, the deletion identified in a girl was transmitted by the asymptomatic father. In the case of the maternally inherited deletion, prenatal diagnosis of dystrophinopathy was proposed for an ongoing pregnancy, whereas the cause of developmental delay in the index case remained unknown. Through these cases, we discussed the challenges of genetic counseling in the family, regarding the predictive issues for male individuals at risk for a muscular dystrophy without precise knowledge of the clinical consequences of some CNVs in the DMD gene.

Fetal skeletal computed tomography: when? How? Why?

PURPOSE: To study the additional role of fetal skeletal computed tomography in suspected prenatal bone abnormalities. MATERIALS AND METHODS: Two centers included in a retrospective study all fetuses who benefited from skeletal computed tomography for a suspected constitutional bone disease or focal dysostosis. RESULTS: A total of 198 patients were included. CT was performed in 112 patients (56%) for an isolated short femur below the third percentile (group A), in 15 patients (8%) for bowed or fractured femur (group B), in 23 patients (12%) for biometric discrepancy between a short femur and increased head circumference (group C) and in 48 patients (24%) for suspected focal dysostosis (group D). CT was interpreted as normal in 126 cases (64%), i.e. 87% in group A, 0% in group B, 65% in group C and 25% in group D. When including only cases with postnatal or postmortem clinical and/or radiological confirmation was available, CT provided additional and/or more accurate information than ultrasound in 20% of cases in group A, 66% in group B, 30% in group C and 72% in group D. Sixty-seven percent of patients in whom CT was interpreted as normal were lost to follow-up. CONCLUSION: In isolated short femur, fetal skeletal CT is normal in the great majority of cases although protocolized follow-up of these babies is absolutely compulsory, as a large proportion is lost to follow-up. Fetal skeletal CT can confirm or improve imaging for the suspected diagnosis in suspected focal dysostosis or constitutional bone disease.

Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia.

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.

[Genotype--phenotype correlation limits in sensorineural hearing loss: case report of a three-year-old child with a bilateral cochleovestibular impairment and a molecular variant of the COCH gene]. / Les limites des relations phénotypes--génotypes dans les surdités neurosensorielles: a propos d'un enfant de 3 ans associant dysfonction cochléovestibulaire bilatérale et variant moléculaire du gène COCH.

Mutations of the COCH gene inherited in an autosomal dominant mode are responsible for late-onset cochleovestibular impairment on both sides. Our objective is to report the youngest patient (3 years) associating a molecular variant of the COCH gene and a cochleovestibular impairment on both sides. The clinical sequence has started with a vestibular dysfunction in a two-year-old child: recurrent rotatory dizziness during 12 months. At the age of 3, a sensorineural hearing loss on both sides has occured associated with spontaneous variation during 6 months. The lack of mutation of the connexin 26, connexin 30 and pendrin genes has reorientated the genetic investigation. A molecular variant of the COCH gene was found in the vWFA2 domain. It was an in-frame deletion predicting the synthesis of an abnormal protein in which 21 aminoacid were missing. Others family members with mutation were asymptomatics. In this isolated case report, the study was in favor of a non pathogenic molecular variant of the COCH gene. For all that, mutations of the COCH gene could be searched in progressive cochleovestibular dysfunctions on both sides in children, even without family affect.

Hippocampal dysgenesis and variable neuropsychiatric phenotypes in patients with Bardet-Biedl syndrome underline complex CNS impact of primary cilia.

The Bardet-Biedl syndrome (BBS) is a rare ciliopathy clinically defined by the association of retinitis pigmentosa, polydactyly, obesity, kidney disease and cognitive impairment. The cognitive functioning, behavioral phenotype, prevalence of psychiatric diseases and memory performances of a cohort of 34 patients with BBS were evaluated and a systemic brain magnetic resonance imaging (MRI) was performed. The patients' cognitive functioning was of marked variable efficiency ranging from normal to disabling performances. Neuropsychological disorders such as slow thought process, attention difficulties and obsessive-compulsive traits were observed. Our main finding was hippocampal dysgenesis, diagnosed by MRI, found in 42.31% of the patients in this cohort. Moreover, we show that BBS proteins are expressed in the human hippocampus and in the human brain in the normal subject. Recent literature in the murine model shows that hippocampal neurogenesis, in particular in the adult mouse, requires an intact primary cilia. These results encourage us to further investigate the possible role of BBS proteins in the hippocampus and related central nervous system structures.

The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.

Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features.