Fetal hydrops is a condition resulting from interstitial fluid accumulation in fetal compartments secondary to increased capillary permeability and characterized by high rates of perinatal mortality and morbidity. Clinical features include skin edema, hydrothorax, pericardial effusion, ascites with or without polyhydramnios, and placental edema. While it may occur as associated feature in multiple disorders, it has been documented to recur in Noonan syndrome, the most common disorder among RASopathies, but also in cardiofaciocutaneous and Costello syndromes. Here, we report on the occurrence of severe hydrops in a newborn heterozygous for the invariant c.4A>G missense change in SHOC2 which underlies Noonan‐like syndrome with loose anagen hair, documenting that it represents a clinically relevant complication in this condition, shared by RASopathies.

Verheij and colleagues were the first to describe two patients harboring de novo overlapping 8q24.3 microdeletions.1 The phenotype was characterized by coloboma, cardiac and renal defect, limb abno...

Noonan‐like syndrome with loose anagen hair (NS/LAH or Mazzanti Syndrome) is caused by a single missense mutation in SHOC2 promoting tN‐myristoylation of the encoded protein. Cardinal features include facial features resembling NS, short stature often associated with proven growth hormone deficiency (GHD), typical ectodermal anomalies, and distinctive behavior. Overall, the clinical features are more severe than those generally observed in NS, even though the phenotype improves with age. We report on growth and pubertal trend in seven patients heterozygous for a mutated SHOC2 allele, treated with long‐term GH‐therapy, and final height (FH) in three of them. They were approximately −3 SDS below the Italian general population standards, they had very low IGF1 levels at baseline and GHD at pharmacological tests. All patients were treated with GH (0.035 mg/kg/day) for a mean period of 8.49 ± 5.72 years. After the 1st year of GH‐therapy, IGF1 level and height velocity had increased. Three of 7 patients reached the FH (−2.34 ± 0.12 SDS) at 18.25 ± 0.73 years, after GH administration for 12.39 ± 2.12 years. Pubertal development was variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the FH. Overall, our data in this small cohort suggest that NS/LAH patients benefit from long‐term GH‐therapy, although they do not show the characteristic catch‐up growth of isolated GHD. While the observed growth and pubertal behavior is consistent with a dysfunction of the hypothalamic‐pituitary‐gonadal axis, the functional link between SHOC2 and the GH/IGF signaling pathways remains to be clarified.

Background: Because CHARGE syndrome is characterized by high clinical variability, molecular confirmation of the clinical diagnosis is of pivotal importance. Most patients have a pathogenic variant in the CHD7 gene; however, variants are distributed throughout the gene and most cases are due to de novo mutations. Often, assessing the pathogenetic effect of a variant can be challenging, requiring the design of a unique assay for each specific case.Method: Here we describe a new CHD7 intronic variant, c.5607+17A>G, identified in two unrelated patients. In order to characterize the molecular effect of the variant, minigenes were constructed using exon trapping vectors.Results: The experimental approach pinpoints the pathogenetic effect of the variant on CHD7 gene splicing, subsequently confirmed using cDNA synthetized from RNA extracted from patient lymphocytes. Our results were further corroborated by the introduction of other substitutions at the same nucleotide position, showing that c.5607+17A>G specifically alters splicing possibly due to the generation of a recognition motif for the recruitment of a splicing effector.Conclusion: Here we identify a novel pathogenetic variant affecting splicing, and we provide a detailed molecular characterization and possible functional explanation.

Razionale. La rete multidisciplinare dell’Emilia-Romagna per lo studio della morte cardiaca improvvisa (MCI) giovanile è stata organizzata a Bologna a partire da giugno 2018 allo scopo di: 1) definire lo spettro delle eziologie e dei meccanismi della MCI nei soggetti di giovane età; 2) uniformare terminologia e categorie diagnostiche; 3) individuare patologie cardiache genetiche potenzialmente ereditarie e definire il contributo dell’analisi genetica post-mortem (cosiddetta autopsia molecolare) al processo diagnostico complessivo; 4) individuare nei familiari di primo grado del soggetto deceduto, attraverso una valutazione sia fenotipica che genotipica, forme precliniche delle patologie in questione e, dove possibile, approntare misure terapeutiche/profilattiche (prevenzione primaria).Materiali e metodi. Nei primi 2 anni di attività (01/06/2018–27/08/2020) sono giunti all’attenzione dell’Unità di Patologia Cardiovascolare del Policlinico S. Orsola-Malpighi di Bologna 50 casi di MCI, provenienti da Centri di Medicina Legale e Anatomia Patologica di gran parte della regione. Risultati. Il 62% dei casi è stato inviato da medici legali, il 36% da Anatomie Patologiche e il 2% dalla famiglia del deceduto. I casi di provenienza medico-legale sono rappresentati nel 70% dei casi da autopsie eseguite su richiesta dell’Autorità Giudiziaria. Dei casi provenienti dalle Anatomie Patologiche, il 55.5% è giunto dalla Banca dei Tessuti Cardiovascolari, nell’ambito del programma regionale di controllo della qualità e sicurezza degli organi e tessuti di donatori multiorgano-multitessuto. L’età media dei soggetti era di 35 ± 13.6 anni (maschi 70%, range: 1-55 anni; mediana: 38 anni). Lo spettro delle diagnosi finali comprende: cuori strutturalmente normali 14%, cardiomiopatie 40%, malattia coronarica 23%, sindrome di Brugada 6%, dissecazione aortica 4%, abuso di sostanze 6%, patologia valvolare 2%, cause miste 2%.Conclusioni. La rete è necessariamente incentrata sulle attività anatomo-patologiche post-mortem, ma non si esaurisce con queste. Se nel 60% dei casi l’esame autoptico patologico è stato determinante per individuare la causa del decesso, negli altri casi una diagnosi finale dettagliata viene raggiunta solo con percorsi più complessi, con coinvolgimento della genetica molecolare, della genetica clinica e della tossicologia.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, affecting approximately 1 in 1000 individuals. This genetically heterogeneous condition is primarily caused by monoallelic pathogenic or likely pathogenic variants in the PKD1 and PKD2 genes, accounting for 78% and 15% of typical cases, respectively. Recently, the application of NGS methods has led to the identification of additional genes associated with ADPKD, which have been incorporated into routine diagnostic testing for detecting phenocopies of the disease. Methods: In this study, targeted NGS (tNGS) analysis of the main cystogenes associated with classic and atypical ADPKD was performed in a cohort of 218 patients clinically diagnosed with cystic nephropathies. Results: Genetic testing identified variants in 175 out of 218 cases (80.3%). Among these, 133 probands (76%) harbored likely pathogenic or pathogenic variants in one or more genes of the panel, while 42 individuals (24%) had a variant of unknown significance (VUS). Specifically, one or more class 4/5 variants in PKD1, PKD2, or both were identified in 111 (83.5%) probands. Remarkably, a pathogenic variant in the IFT140 gene was identified in 14 index cases (8% of positive individuals, 6.4% of the global cohort): 10 distinct loss-of-function (LoF) variants were identified (including four frameshift variants, four nonsense variants, and two splice site defects); one individual carried a second IFT140 missense variant classified as VUS. Furthermore, five affected family members were found to carry a P/LP LoF variant in IFT140. Conclusions: Our data support that IFT140 heterozygous IFT140 LoF variants result in an atypical, mild form of ADPKD, consisting of bilateral kidney cysts and renal functional decline at older ages. Furthermore, we describe the second pediatric patient with a mild form of ADPKD due to an IFT140 variant and discuss hyperuricemia as a previously unappreciated feature of this condition.