Lidia Pezzani

Is it time to change the neurofibromatosis 1 diagnostic criteria

Neurofibromatosis 1 is a complex inherited neurocutaneous disease that is often difficult to diagnose early because of its age-dependent presentation. The diagnosis is also extremely difficult to communicate to patients and their parents because of the diseases clinical variability, unpredictable evolution, and uncertain prognosis. Since 1988, the year of publication of the last Consensus Conference statement concerning the diagnosis of neurofibromatosis 1, our understanding of the disease has naturally increased and, in addition to the availability of increasingly precise molecular analyses, some new clinical signs have been reported such as anaemic nevi, unidentified bright objects, choroidal hamartomas, and a typical neuropsychological phenotype. We critically review the current diagnostic criteria, and suggest the addition of new signs on the basis of published findings and our own clinical experience. This proposal aims to improve diagnostic power in paediatric age, securing a better and more reliable healthcare transition toward adult age. We finally recommend a new Consensus Conference in order to revise the diagnostic criteria, possibly differentiated by age of presentation.

Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management

BackgroundRubinstein-Taybi syndrome (RSTS) is an extremely rare autosomal dominant genetic disease, with an estimated prevalence of one case per 125,000 live births. RSTS is characterized by typical facial features, microcephaly, broad thumbs and first toes, intellectual disability, and postnatal growth retardation. However, no standard diagnostic criteria are available for RSTS. In this review, we summarized the clinical features and genetic basis of RSTS and highlighted areas for future studies on an appropriate diagnostic protocol and follow-up care for RSTS.DiscussionRSTS is primarily characterized by delayed growth in height and weight, microcephaly, dysmorphic facial features, and broad thumbs and big toe. Over 90% RSTS individuals with disabilities survive to adulthood, but healthcare for these patients is particularly complex, time-consuming, and costly. In addition, no standard diagnostic criteria and follow-up care guidelines are available for RSTS. It has been shown that mutations in the genes encoding the cyclic-AMP-regulated enhancer binding protein (CREBBP) and the E1A-binding protein p300 (EP300) contributed to the development of RSTS. Therefore, genetic tests are useful for the diagnosis of RSTS, although most RSTS cases are currently diagnosed based on clinical features.SummaryThe clinical features of RSTS have been extensively studied, which significantly contributes to the diagnosis of this extremely rare syndrome. However, the pathogenesis and genotype-phenotype associations of RSTS are largely unknown. Therefore, multicenter studies and international cooperation are highlighted for better understanding of this disease, establishing standard diagnostic criteria, and providing professional management and follow-up care of RSTS.

Beckwith–Wiedemann and IMAGe syndromes: two very different diseases caused by mutations on the same gene

Genomic imprinting is an epigenetically regulated mechanism leading to parental-origin allele-specific expression. Beckwith–Wiedemann syndrome (BWS) is an imprinting disease related to 11p15.5 genetic and epigenetic alterations, among them loss-of-function CDKN1C mutations. Intriguing is that CDKN1C gain-of-function variations were recently found in patients with IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies). BWS and IMAGe share an imprinted mode of inheritance; familial analysis demonstrated the presence of the phenotype exclusively when the mutant CDKN1C allele is inherited from the mother. Interestingly, both IMAGe and BWS are characterized by growth disturbances, although with opposite clinical phenotypes; IMAGe patients display growth restriction whereas BWS patients display overgrowth. CDKN1C codifies for CDKN1C/KIP2, a nuclear protein and potent tight-binding inhibitor of several cyclin/Cdk complexes, playing a role in maintenance of the nonproliferative state of cells. The mirror phenotype of BWS and IMAGe can be, at least in part, explained by the effect of mutations on protein functions. All the IMAGe-associated mutations are clustered in the proliferating cell nuclear antigen-binding domain of CDKN1C and cause a dramatic increase in the stability of the protein, which probably results in a functional gain of growth inhibition properties. In contrast, BWS mutations are not clustered within a single domain, are loss-of-function, and promote cell proliferation. CDKN1C is an example of allelic heterogeneity associated with opposite syndromes.

Preliminary evaluation of cord blood platelet gel for the treatment of skin lesions in children with dystrophic epidermolysis bullosa

The common clinical manifestations of EB are mechanical fragility of the skin, blister formation, and abnormal wound healing, but the severity of the skin lesions varies depending on the distinct type of the disease. Junctional EB and dystrophic EB (DEB), the most severe types of EB diseases, usually cause chronic pain and discomfort that can significantly reduce the quality of life of affected

Cord blood platelet gel treatment of dystrophic recessive epidermolysis bullosa

Epidermolysis bullosa (EB) is comprised of a group of hereditary mechanobullous disorders that are characterised by extremely fragile skin and mucous membranes. This results in blister formation and non-healing wounds. This case report describes the results of an innovative treatment of two large skin lesions in a newborn with dystrophic recessive EB (DEB) who experienced bacterial superinfections and progressive anaemisation. The lesions were treated with platelet gels derived from allogeneic cord blood (cord blood platelet gel, CBPGs). The skin lesions were clinically evaluated and treated with CBPG weekly until they completely healed. The first and second lesion required CBPG applications for 2 and 4 weeks, respectively. Both lesions were monitored weekly for 6 weeks after the last CBPG application, and no significant relapses were observed during the follow-up period. This case indicates that CBPG is an effective and safe therapeutic option for managing newborns with DEB, particularly as treatment and prevention of fluid loss and superinfection.

7p22.1 microduplication syndrome: Refinement of the critical region

7p22.1 microduplication syndrome is mainly characterized by developmental and speech delay, craniofacial dysmorphisms and skeletal abnormalities. The minimal critical region includes two OMIM genes: ACTB and RNF216. Here, we report on a girl carrying the smallest 7p22.1 microduplication detected to date, contributing to the delineation of the clinical phenotype of the 7p22.1 duplication syndrome and to the refinement of the minimal critical region. Our patient shares several major features of the 7p22.1 duplication syndrome, including craniofacial dysmorphisms and speech and motor delay, but she also presents with renal anomalies. Based on present and published dup7p22.1 patients we suggest that renal abnormalities might be an additional feature of the 7p22.1 microduplication syndrome. We also pinpoint the ACTB gene as the key gene affecting the 7p22.1 duplication syndrome phenotype.

Nevoid follicular mucinosis: a new type of hair follicle nevus

Follicular mucinosis represents a term for a histopathologic reaction pattern in follicular epithelium. It is a characteristic of alopecia mucinosa. However, it may also occur in a variety of unrelated conditions. Epidermal nevi are considered to be hamartomatous disorders and they can show a predominant component of non‐organoid (keratinocytes) and/or organoid nevi. All the cases of epidermal nevi described with mucin deposits until now are reported as mucinous nevus or mucinous eccrine nevus; in the first type of disorder, diffuse mucin deposition is only seen in the papillary dermis, and in the second type, the mucin is found around the proliferation of eccrine structures. We believe this is the first reported case of epidermal nevus along Blaschkos lines exhibiting typical microscopic findings of mucinosis exclusively distributed inside the follicular epithelia.

Is cutis verticis gyrata-intellectual disability syndrome an underdiagnosed condition? A case report and review of 62 cases

Cutis Verticis Gyrata‐Intellectual Disability (CVG‐ID) syndrome is a rare neurocutaneous syndrome characterized by intellectual disability and scalp folds and furrows that are typically absent at birth and are first noticed after puberty. First reported in 1893, the syndrome was mainly identified in subjects living in psychiatric institutions, where it was found to have a prevalence of up to 11.4%. Most patients were reported in the literature during the first half of the 20th century. CVG‐ID is now a less reported and possibly under‐recognized syndrome. Here, we report a patient with CVG‐ID that was diagnosed using the novel approach of magnetic resonance imaging and we conduct a systematic review of all patients reported in the last 60 years, discussing the core clinical features of this syndrome.

Intellectual Disability: When the Hypertrichosis Is a Clue.

The skin and the central and peripheral nervous system both derive from the ectoderm ridge. Therefore, several syndromes characterized by the presence of intellectual disability (ID) can be associated with specific congenital cutaneous manifestations. In this review, we list some of the most frequent diseases characterized by the presence of ID associated with hirsutism, which might be an incentive for the clinicians to pay attention to the ectodermal annexes in patients with ID.

A Novel Intragenic Deletion in Ophn1 in A Boy with Developmental Delay, Strabismus and Cerebellar Hypoplasia

X-linked intellectual disability (XLID) is a notably heterogeneous condition and often poses a diagnostic challenge; it is more common in males than females, indicating a role of defects on the X chromosome. The oligophrenin-1 (OPHN1) gene on Xq12 is one of the genes responsible for a syndromic form of XLID characterized by specific brain anomalies and distinctive facial features.