Unique Features of Cardiovascular Involvement and Progression in Children with Marfan Syndrome Justify Dedicated Multidisciplinary Care.

Marfan syndrome (MIM: # 154700; MFS) is an autosomal dominant disease representing the most common form of heritable connective tissue disorder. The condition presents variable multiorgan expression, typically involving a triad of cardiovascular, eye, and skeletal manifestations. Other multisystemic features are often underdiagnosed. Moreover, the disease is characterized by age related penetrance. Diagnosis and management of MFS in the adult population are well-described in literature. Few studies are focused on MFS in the pediatric population, making the clinical approach (cardiac and multiorgan) to these cases challenging both in terms of diagnosis and serial follow-up. In this review, we provide an overview of MFS manifestations in children, with extensive revision of major organ involvement (cardiovascular ocular and skeletal). We attempt to shed light on minor aspects of MFS that can have a significant progressive impact on the health of affected children. MFS is an example of a syndrome where an early personalized approach to address a dynamic, genetically determined condition can make a difference in outcome. Applying an early multidisciplinary clinical approach to MFS cases can prevent acute and chronic complications, offer tailored management, and improve the quality of life of patients.

High Prevalence of Scoliosis in a Large Cohort of Patients with Prader-Willi Syndrome.

The characteristics of scoliosis were investigated in a large cohort of children and adults with Prader-Willi syndrome (PWS), analysing the role of age, gender, puberty, body mass index (BMI), genotype and growth hormone therapy (GHT) on its onset and severity. A retrospective cross-sectional study was performed in 180 patients with genetically confirmed PWS (96 females), aged 17.6 ± 12 years. Eighty-five subjects (47%) were obese. One hundred and fifty subjects (83.3%) were on GHT, while 30 patients had never been treated. Overall, 150 subjects (83.3%) were affected by scoliosis, 80.2% of children and adolescents and 87.8% of adults. A mild degree of scoliosis was observed in 58 patients (38.7%), moderate in 43 (28.7%) and severe in 49 (32.6%). Median age at diagnosis of scoliosis was 6.3 years, while the severe forms were diagnosed earlier (median age: 3.8 years). The cumulative probability at 5 years of age was equal to 0.403 and almost doubled at 15 years. No significant associations were found between scoliosis and genotype, gender, pubertal stage, GHT and BMI. A corset was prescribed to 75 subjects (50%) at a median age of 7.5 years, while 26 subjects (17.3%) underwent surgery at a median age of 13.1 years. Our data indicate that scoliosis is one of the major concerns for PWS patients that increases with age, and therefore suggest the need for regular systematic monitoring of spinal deformity from paediatric age.

Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart?

Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives' recurrence risk calculation. The previous points represent a cornerstone in patients' empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective "autophagy" process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.

Management of motor rehabilitation in individuals with muscular dystrophies. 1st Consensus Conference report from UILDM - Italian Muscular Dystrophy Association (Rome, January 25-26, 2019).

Muscular dystrophy (MD) is a group of neuromuscular diseases characterized by progressive muscle weakness due to various mutations in several genes involved in muscle structure and function. The age at onset, evolution and severity of the different forms of MD can vary and there is often impairment of motor function and activities of daily living. Although there have been important scientific advances with regard to pharmacological therapies for many forms of MD, rehabilitation management remains central to ensuring the patient's psychophysical well-being. Here we report the results of an Italian consensus conference promoted by UILDM (Unione Italiana Lotta alla Distrofia Muscolare, the Italian Muscular Dystrophy Association) in order to establish general indications and agreed protocols for motor rehabilitation of the different forms of MD.

Expanding the Clinical and Mutational Spectrum of the PLP1-Related Hypomyelination of Early Myelinated Structures (HEMS).

The PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. Mutations in PLP1 cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel PLP1 mutations in exon 3B detected by targeted next-generation sequencing. Patients experienced psychomotor delay or nystagmus in the first year of age and then developed ataxic-spastic or ataxic syndrome, compatible with a phenotype of intermediate severity in the spectrum of PLP1-related disorders. Regression occurred at the beginning of the third decade of the eldest patient. Extrapyramidal involvement was rarely observed. Brain MRI confirmed the involvement of structures that physiologically myelinate early, although the pattern of abnormalities may differ depending on the age at which the study is performed. These new cases contribute to expanding the phenotypic and genotypic spectrum of HEMS. Additional studies, especially enriched by systematic functional evaluations and long-term follow-up, are welcome to better delineate the natural history of this rare hypomyelinating leukodystrophy.

Assessing and treating pain associated with stroke, multiple sclerosis, cerebral palsy, spinal cord injury and spasticity. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

Pain is a common and disabling symptom in patients with stroke, multiple sclerosis (MS), cerebral palsy (CP), spinal cord injury (SCI) and other conditions associated with spasticity, but data on its prevalence, and natural history, as well as guidelines on its assessment and treatment in the field of neurorehabilitation, are largely lacking. The Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) searched and evaluated current evidence on the frequency, evolution, predictors, assessment, and pharmacological and non-pharmacological treatment of pain in patients with stroke, MS, CP, SCI and other conditions associated with spasticity. Patients with stroke, MS, CP, and SCI may suffer from pain related to spasticity, as well as nociceptive and neuropathic pain (NP), whose prevalence, natural history, impact on functional outcome, and predictors are only partially known. Diagnosis and assessment of the different types of pain in these patients is important, because their treatment may differ. Botulinum neurotoxin is the first choice treatment for spasticity, while some antidepressant and antiepileptic drugs may be effective on NP, but pharmacological treatment varies according to the underlying disease. In most cases, a single therapy is not sufficient to treat pain, and a multidisciplinary approach, which include pharmacological and non-pharmacological treatments is needed. Further studies, and in particular randomized controlled trials, are needed on these topics.