Long-term follow-up in a pediatric patient with Ligneous Conjunctivitis due to PLG gene mutation in topical plasminogen treatment after successful use of ocular prosthesis for aesthetic rehabilitation: a case report.

BACKGROUND: Ligneous Conjunctivitis (LC) is the most common clinical manifestation of Type I Plasminogen deficiency (T1PD; OMIM# 217090), and it is characterized by the formation of pseudomembranes (due to deposition of fibrin) on the conjunctivae leading to progressive vision loss. In past times, patients with LC were treated with surgery, topical anti-inflammatory, cytostatic agents, and systemic immunosuppressive drugs with limited results (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022, Surv Ophthalmol 48:369-388, 2003, Blood 131:1301-1310, 2018). The surgery can also trigger the development of membranes, as observed in patients needing ocular prosthesis (Surv Ophthalmol 48:369-388, 2003). Treatment with topical purified plasminogen is used to prevent pseudomembranes formation (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022). CASE PRESENTATION: We present the case of a sixteen-year-old girl with LC with severe left eye involvement. We reported the clinical conditions of the patient before and after the use of topical plasminogen eye drops and described the treatment schedule allowing the surgical procedure for the pseudomembranes debulking and the subsequent use of ocular prosthesis for aesthetic rehabilitation. CONCLUSIONS: The patient showed a progressive response to the topical plasminogen, with a complete absence of pseudomembrane formation at a twelve-year follow-up, despite using an ocular prosthesis.

Characterization of Cognitive, Language and Adaptive Profiles of Children and Adolescents with Malan Syndrome.

Malan Syndrome (MS) is an ultra-rare overgrowth genetic syndrome due to heterozygous variants or deletions in the Nuclear Factor I X (NFIX) gene. It is characterized by an unusual facial phenotype, generalized overgrowth, intellectual disability (ID) and behavioral problems. Even though limitations in cognitive and adaptive functioning have been previously described, systematic studies on MS cohorts are still lacking. Here, we aim to define the cognitive and adaptive behavior profile of MS children and adolescents, providing quantitative data from standardized evaluations. Subjects included in this study were evaluated from October 2020 to January 2022 and the study is based on a retrospective data archive: fifteen MS individuals were recruited and underwent evaluation with Wechsler Intelligence Scales, Leiter International Performance Scales and Griffith Mental Development Scales for cognitive profiles and with Vineland Adaptive Behavior Scales-II Edition (VABS-II) for adaptive functioning. Language skills and visuomotor integration abilities were assessed too. Comparisons and correlations between scales and subtests were performed. All the assessed MS individuals showed both low cognitive and adaptive functioning. One subject presented with mild ID, five had moderate ID and eight showed severe ID. One female toddler received a diagnosis of psychomotor delay. Linguistic skills were impaired in all individuals, with language comprehension relatively more preserved. Results revealed significant differences between VABS-II subdomains and a strong relationship between cognitive and adaptive functioning. All subjects exhibited mild to moderate ID and adaptive behavior lower than normal, with communication skills being the most affected. Regarding the daily living skills domain, personal and community subscale scores were dramatically lower than for the domestic subdomain, highlighting the importance of considering behavior within developmental and environmental contexts. Our cognitive and adaptive MS characterization provides a more accurate quantitative MS profiling, which is expected to help clinicians to better understand the complexity of this rare disorder.

Expanding phenotype of FAM111B-related disease focusing on liver involvement: Literature review, report of a case with end-stage liver disease and proposal for a new acronym.

POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis is a congenital multisystem disorder due to FAM111B dominant variants. We present a literature review focusing on the frequency and the impact of hepatic involvement and a case report of a patient with severe end-stage liver disease. Whole exome sequencing (WES) was conducted on the proband and his parents. A de novo FAM111B: c.1879A > G; (p.Arg627Gly) variant was identified. Hepatic involvement is present in 11 out of the 30 patients described in the literature, with different levels of dysfunction ranging from mild transaminitis to liver fibrosis found in three different cases by liver biopsies. Liver involvement seems to be a significant cause of morbidity. We propose to modify the previous acronym in POIK-TMPL: including POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis/pancreas insufficiency and cancer, liver involvement/lymphedema. Moreover, we suggest screening patients with FAM111B variants for liver involvement from the first month of life and continue with an appropriate follow-up. Further studies are needed to better understand this frequent complication.

A deep phenotyping experience: up to date in management and diagnosis of Malan syndrome in a single center surveillance report.

BACKGROUND: Malan syndrome (MALNS) is a recently described ultrarare syndrome lacking guidelines for diagnosis, management and monitoring of evolutive complications. Less than 90 patients are reported in the literature and limited clinical information are available to assure a proper health surveillance. RESULTS: A multidisciplinary team with high expertise in MALNS has been launched at the "Ospedale Pediatrico Bambino Gesù", Rome, Italy. Sixteen Italian MALNS individuals with molecular confirmed clinical diagnosis of MALNS were enrolled in the program. For all patients, 1-year surveillance in a dedicated outpatient Clinic was attained. The expert panel group enrolled 16 patients and performed a deep phenotyping analysis directed to clinically profiling the disorder and performing critical revision of previously reported individuals. Some evolutive complications were also assessed. Previously unappreciated features (e.g., high risk of bone fractures in childhood, neurological/neurovegetative symptoms, noise sensitivity and Chiari malformation type 1) requiring active surveillance were identified. A second case of neoplasm was recorded. No major cardiovascular anomalies were noticed. An accurate clinical description of 9 new MALNS cases was provided. CONCLUSIONS: Deep phenotyping has provided a more accurate characterization of the main clinical features of MALNS and allows broadening the spectrum of disease. A minimal dataset of clinical evaluations and follow-up timeline has been proposed for proper management of patients affected by this ultrarare disorder.

Molecular tools for the genomic assessment of oocyte's reproductive competence.

The most important factor associated with oocytes' developmental competence has been widely identified as the presence of chromosomal abnormalities. However, growing application of genome-wide sequencing (GS) in population diagnostics has enabled the identification of multifactorial genetic predispositions to sub-lethal pathologies, including those affecting IVF outcomes and reproductive fitness. Indeed, GS analysis in families with history of isolated infertility has recently led to the discovery of new genes and variants involved in specific human infertility endophenotypes that impact the availability and the functionality of female gametes by altering unique mechanisms necessary for oocyte maturation and early embryo development. Ongoing advancements in analytical and bioinformatic pipelines for the study of the genetic determinants of oocyte competence may provide the biological evidence required not only for improving the diagnosis of isolated female infertility but also for the development of novel preventive and therapeutic approaches for reproductive failure. Here, we provide an updated discussion and review of the progresses made in preconception genomic medicine in the identification of genetic factors associated with oocyte availability, function, and competence.

Familial Mediterranean fever: breaking all the (genetic) rules.

OBJECTIVE: FMF is an inherited autoinflammatory syndrome, characterized by attacks of painful periodic fever caused by diffuse serositis and risk of secondary amyloidosis due to IL-1ß-mediated inflammation. The disease appears to be transmitted through autosomal recessive mutations in the MEFV gene encoding the pyrin protein Although more than 300 variants have been reported worldwide so far, their association with symptom severity, the relative frequencies in different populations and the disease penetrance are far from being completely understood. We investigated genotype-phenotype correlations in two large nuclear families and verified whether commonly used web-based tools can usefully predict variant pathogenicity in FMF. METHODS: Peripheral blood samples were obtained from 15 patients of two families who had been diagnosed with FMF according to international criteria. The entire MEFV coding region was sequenced in all subjects, and 179 MEFV variants were surveyed with five different pathogenicity predictors. RESULTS: The inheritance of FMF could not be explained by traditional autosomal recessivity in both families. In silico tools demonstrated a significant association of variants' pathogenicity with their position along the coding sequence but not with variants' frequency. CONCLUSION: By describing two large families with paradigmatic complexity of FMF genetics, we conclude that established concepts in assessing the causative role of variants identified in mutation screening cannot be easily translated into appropriate genetic counselling in FMF. Furthermore, we demonstrate that variants frequently associated with severe disease are not predicted to significantly impact protein function using in silico algorithms.