Novel Variant in Exon 3 of the BMP4 Gene Resulted in Ectopic Posterior Pituitary, Craniocervical Junction Dysmorphism and Limb Anomaly

Introduction. Pituitary differentiation involves a large number of transcription factors. In particular, BMP4 expression is fundamental for pituitary gland commitment from the ventral diencephalon, suppressing Shh expression in Rathke's pouch. Pathogenic variants in BMP4 are reported in the literature with a broad phenotypic spectrum, including pituitary and brain malformations. Case Presentation. A five-year-old girl came to medical attention following a mild cervical trauma with onset of cervical pain. On clinical examination at birth, postaxial polydactyly type B of the left hand was observed and removed at 10 months of age. A cervical radiography was performed, and a suspicion of craniocervical junction malformation was made. A magnetic resonance imaging of the cervical spine was made, showing an ectopic posterior pituitary, associated with dysmorphism of the craniocervical junction. The anthropometric parameters were pubertal Tanner stage 1, weight 16 kg (z-score: -1.09), height 107 cm (z-score: -0.76), and BMI 14 kg/m(2) (z-score: -0.92). Normal hormonal assessment was detected. Genetic analysis via next generation sequencing showed a novel de novo heterozygous variant (c.277 G > T, p.Glu93*) in exon 3 of BMP4. Discussion. We described a novel mutation in BMP4, resulting in ectopic posterior pituitary with normal hormonal assessment, associated to craniocervical junction dysmorphism and limb anomaly. It is important to monitor patient's growth and puberty and to screen the onset of symptoms related to the deficiency of one or more anterior as well as posterior pituitary hormones

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluati

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

Currarino syndrome and microcephaly due to a rare 7q36.2 microdeletion: a case report

Abstract Background Currarino syndrome is a rare condition characterized by presacral mass, anorectal malformation and sacral dysgenesis. Case presentation We report the case of a child that presented chronic constipation, encopresis and mycrocephaly. The characteristics were initially compatible with a case of functional constipation and a therapy with polyethylene glycol was prescribed. After a year, because of poor response, a plain abdominal X-ray was performed, detecting sacrum abnormalities. Finally, a CGH-array analysis was performed and a form of Currarino Syndrome caused by a rare 7q36 microdeletion, was diagnosed. Conclusion Occult spinal dysraphism should be suspected in case of poor polyethylene glycol responder constipation, even when evident sacral abnormalities on the physical examination are not detected

Semiological study of ictal affective behaviour in epilepsy and mental retardation limited to females (EFMR)

Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [Published with video sequences

Semiological study of ictal affective behaviour in epilepsy and mental retardation limited to females (EFMR)

Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [Published with video sequences