RESUMEN
BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.
Asunto(s)
Anomalías Múltiples/epidemiología , Anomalías Múltiples/fisiopatología , Enfermedades del Desarrollo Óseo/epidemiología , Enfermedades del Desarrollo Óseo/fisiopatología , Anomalías Craneofaciales/epidemiología , Anomalías Craneofaciales/fisiopatología , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/fisiopatología , Trastornos Mentales/epidemiología , Displasia Septo-Óptica/epidemiología , Displasia Septo-Óptica/fisiopatología , Trastornos del Habla/epidemiología , Adaptación Psicológica , Adolescente , Adulto , Niño , Preescolar , Comorbilidad , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Trastornos Mentales/fisiopatología , Países Bajos/epidemiología , Fenotipo , Trastornos del Habla/fisiopatología , Síndrome , Adulto JovenRESUMEN
Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.
Asunto(s)
Encéfalo/metabolismo , Megalencefalia/genética , Síndrome de Smith-Lemli-Opitz/genética , Serina-Treonina Quinasas TOR/genética , Adolescente , Encéfalo/fisiopatología , Proliferación Celular/genética , Niño , Fosfatidilinositol 3-Quinasa Clase I/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Megalencefalia/diagnóstico por imagen , Megalencefalia/fisiopatología , Mutación , Plasticidad Neuronal/genética , Proteínas Proto-Oncogénicas c-akt/genética , Síndrome de Smith-Lemli-Opitz/diagnóstico por imagen , Síndrome de Smith-Lemli-Opitz/fisiopatología , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genéticaRESUMEN
Mutations in PIK3R1 gene have been associated to two different conditions: a primary immunodeficiency, called APDS2, of recent description and SHORT syndrome. 47 patients with APDS2 have been reported to date, only one of them sharing both PIK3R1-related phenotypes. Here we describe two more patients affected by APDS2 and SHORT syndrome, which highlights that this association may not be so infrequent. We recommend that patients with mutations in PIK3R1 gene should be assessed by both clinical immunologists and clinical geneticists.
Asunto(s)
Trastornos del Crecimiento/genética , Hipercalcemia/genética , Síndromes de Inmunodeficiencia/genética , Enfermedades Metabólicas/genética , Nefrocalcinosis/genética , Fosfatidilinositol 3-Quinasas/genética , Niño , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase Ia , Humanos , Lactante , Masculino , Mutación , Enfermedades de Inmunodeficiencia PrimariaAsunto(s)
Anomalías Múltiples/genética , Coloboma/genética , Cardiopatías Congénitas/genética , Mutación , Factores de Empalme de ARN/genética , Proteínas Represoras/genética , Anomalías Múltiples/metabolismo , Preescolar , Coloboma/metabolismo , Femenino , Cardiopatías Congénitas/metabolismo , Humanos , Masculino , Análisis de Secuencia de ADNRESUMEN
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype-phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype-phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at-risk.
