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

Abstract

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.

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

“…This result is not surprising since visuomotor integration allows coordination of visual data about the body, the extracorporeal space and the relative position of the body in space, with movements of the whole body or part of it, in order to guarantee coordinated, smooth and effective motor sequences. MS subjects displayed impaired visuomotor, visuoperceptive and visuospatial integration, which may be attributable to ocular motility abnormalities and lower visual acuity and/or to cortical-subcortical visual integration deficits [19], in line with some other previous reports [7].…”

“…Fifteen Italian subjects with molecularly confirmed diagnosis of MS (M/F = 9/6), whose pediatric management has already been described [ 19 ], were included in this study. The clinical phenotype of 6 individuals of this cohort (Subjects 3, 4, 6, 8, 11 and 12, Table 1 ) was reported by Priolo et al [ 2 ], while 9 individuals (Subjects 1, 2, 5, 7, 9, 10, 13, 14, 15, Table 1 ) had not previously been described.…”

Sotos Syndrome Type 1 and Type 2: Case Series of 4 Pediatric Patients with Variants in NSD1 and NFIX Genes

“…The estimated prevalence at birth of SOTOS1 is approximately 1 in 10,000 to 14,000 newborns [9], while of SOTOS2 less than 1 in 1,000,000 [3].…”

Behavioral profiling in children and adolescents with Malan syndrome

“…Individuals with NFIX microdeletions present with a significantly higher frequency of epilepsy and EEG anomalies than those carrying NFIX intragenic variants, possibly because of the involvement of adjacent genes contributing to the clinical phenotype in the frame of a contiguous gene disorder (2). No other clinically relevant genotype-phenotype correlation has been reported (8).…”

“…Increased susceptibility to tibial fractures has also been observed. Facial features have been well characterized and are represented by a long and narrow face with a triangular shape, a high and prominent forehead, deeply set eyes, a depressed nasal bridge, a short nose with anteverted nares, everted lower lip with a small mouth and prognathia/prominent chin becoming more evident in adulthood (2,8) Visual problems are frequent, especially strabismus, refractive errors, nystagmus, and optic nerve hypoplasia (8). Generalized hypotonia with swallowing difficulties may be present at birth (1,2,8).…”