Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.

[CDAGS syndrome (craniostenosis, deafness, anal abnormalities and genitourinary malformations with skin rash)]. / Syndrome CDAGS (craniosténose, surdité, anomalie anale et génito-urinaire avec éruption cutanée).

INTRODUCTION: CDAGS syndrome (craniosynostosis, deafness, anal and genitourinary abnormality with rash) has been reported in 8 families of different geographical origins since 1981. No genes have been identified to date. PATIENTS AND METHODS: The patient is a girl born at 40 weeks of amenorrhea after a normal pregnancy. She was born to non-consanguineous parents and there was no significant family history. At birth, she presented craniosynostosis with a form of premature coronal suture. When she was 3 months old, she presented an eczematous facial rash. At 11 months, a skin biopsy showed lichenoid dermatosis with epidermal atrophy associated with ortho- and para-keratotic hyperkeratosis. She had sparse hair, eyelashes and eyebrows. Her initial psychomotor development was normal. No other malformations were observed. At 6 years, she presented pale pink, reticulated, erythematous plaques around healthy bands of skin on her throat and chin. Lesions on the elbows, knees and buttocks were linear and keratotic with no atrophy or telangiectasia. At 7 years, she had learning difficulties and delayed speech. Genetic assessment revealed no abnormalities. DISCUSSION: The specific dermatologic aspect combined with craniosynostosis suggested a possible diagnosis of CDAGS syndrome, even in the absence of urogenital or anal lesions. This syndrome may take numerous different forms. The appearance of porokeratosis previously noted was not found here. The underlying genetic substratum of this syndrome is not known as yet and additional genetic studies should be considered.

Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis.

Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.

Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Emergency management of a congenital teratoma of the oral cavity at birth and three-year follow-up.

Teratomas are congenital malformations that are rarely located in the head and neck region. We report a case of congenital teratoma of the oral cavity, which was causing an airway obstruction and was treated at the time of birth. This teratoma was discovered at 27 gestational weeks by ultrasonography. A multidisciplinary team was consulted for antenatal diagnosis; the options of therapeutic abortion or management of the birth with the prevention of respiratory distress were debated. However, preterm labour at 32 gestational weeks accelerated the parental and the medical decisions. The parents agreed to the birth. The various disciplines coordinated their work, and the predefined treatment plan for clearing the airway obstruction was applied to manage the birth. The reestablishment of patency of the airway was performed during delivery and removal of the tumour was performed immediately afterwards. The follow-up of this case over 3 years is also presented.