Familial neurohypophyseal diabetes insipidus: clinical, genetic and functional studies of novel mutations in the arginine vasopressin gene.

PURPOSE: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder characterized by childhood-onset progressive polyuria and polydipsia due to mutations in the arginine vasopressin (AVP) gene. The aim of the study was to describe the clinical and molecular characteristics of families with neurohypophyseal diabetes insipidus. METHODS: Five Portuguese families with autosomal dominant FNDI underwent sequencing of the AVP gene and the identified mutations were functionally characterized by in vitro studies. RESULTS: Three novel and two recurrent heterozygous mutations were identified in the AVP gene. These consisted of one initiation codon mutation in the signal peptide coding region (c.2T > C, p.Met1?), three missense mutations in the neurophysin II (NPII) coding region (c.154T > C, p.Cys52Arg; c.289C > G, p.Arg97Gly; and c.293G > C, p.Cys98Ser), and one nonsense mutation in the NPII coding region (c.343G > T, p.Glu115Ter). In vitro transfection of neuronal cells with expression vectors containing each mutation showed that the mutations resulted in intracellular retention of the vasopressin prohormone. Patients showed progressive symptoms of polyuria and polydipsia, but with wide variability in severity and age at onset. No clear genotype-phenotype correlation was observed. CONCLUSION: The intracellular accumulation of mutant vasopressin precursors supports the role of cellular toxicity of the mutant proteins in the etiology of the disorder and explains the progressive onset of the disorder. These findings further expand the AVP mutational spectrum in FNDI and contribute to the understanding of the molecular pathogenic mechanisms involved in FNDI.

Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations.

Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

Genomic imbalances defining novel intellectual disability associated loci.

BACKGROUND: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). RESULTS: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. CONCLUSIONS: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

Bilateral perisylvian polymicrogyria and chromosome 1 anomaly.

Polymalformative syndromes are always a clinical challenge for their complexity and sometimes for their rarity. Authors present the case of a girl with peculiar facies, macrocephaly, axial hypotonia, and severe development delay. Cerebral magnetic resonance showed polymicrogyria. Cytogenetics revealed a 46,XX,der(1)(qter-->p36.13::q42.3-->qter) karyotype. This is the third case described to date. Isolated partial deletions or trisomy, although rare, are more frequently reported. None of these genetic findings has ever been related with polymicrogyria. Molecular cytogenetic characterization was in this case of great value.

Cat eye syndrome and growth hormone deficiency with pituitary anomalies: a case report and review of the literature.

Cat eye syndrome is a rare congenital disease characterized by the existence of a supernumerary chromosome derived from chromosome 22, with a variable phenotype comprising anal atresia, coloboma of the iris and preauricular tags or pits. We report a girl with cat eye syndrome, presenting short stature, with growth hormone deficiency due to posterior pituitary ectopia. Short stature is a common feature of this syndrome, and the association with a structural pituitary anomaly has been described, however growth hormone deficiency and the underlying mechanisms are rarely reported. A review on short stature and growth hormone deficiency in cat eye syndrome is conducted.

Kallmann syndrome in a female adolescent: a new mutation in the FGFR1 gene.

The Kallmann syndrome is characterised by the association of hypogonadotropic hypogonadism and hypo/anosmia. It represents a phenotypically and genotypically heterogeneous clinical entity, with six genes identified so far in the literature-KAL1, FGFR1, PROKR2, PROK2, CHD7 and FGF8. Mutations in the FGFR1 gene can be found in approximately 10% of the patients. The authors present the case of a female adolescent with hypogonadotropic hypogonadism and impaired olfactory acuity in the presence of hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs. The molecular analysis of the fibroblast growth factor receptor 1 identified a heterozygous mutation c.1377_78insA (p.V460SfsX3) in exon 10 of FGFR1 gene. This mutation has not yet been reported in the literature. A theoretical review of clinical features and therapeutic approach of this syndrome is also presented.

Pertussis in Portugal - time for a new strategy.

The introduction of routine vaccination against Bordetella pertussis led to a drastic decline in the number of reported cases of pertussis. Nevertheless, a gradual increase in pertussis notifications has been observed in the last years, and political vaccination changes have been conducted in some countries. Pertussis epidemiology is reviewed, taking into account mathematical models studies concerning new vaccinal strategies for pertussis prevention and new international recommendations. Regarding Portugal, the need for a "booster" in adolescence is emphasized, and other recommendations for pertussis control are suggested.