ABSTRACT
BACKGROUND: Loeys-Dietz syndrome (LDS) is a congenital multisystem disorder affecting the cardiovascular and musculoskeletal system. Limited data have reported neurodevelopmental (ND) issues in LDS. AIMS: To determine the extent of ND issues in patients with LDS. METHODS: A prospective study was performed of LDS patients or their caregivers. The study included data collected via an online survey of age-specific questions. Standard statistical methods were used for baseline and demographic characteristics, as well as group comparisons. OUTCOMES: Data were obtained from 67 patients with LDS (54% female). Median age was 14.9 years. Gene mutations included TGFBR1 (39%), TGFBR2 (40%), SMAD3 (7%), and unknown (14%). Motor delays (30%, 18/61) and hypotonia (63%, 37/60) occurred frequently. Physical (62%, 39/62), occupational (41%, 23/56), and speech therapies (34%, 20/58) were common. Feeding issues were common (41%, 23/56). TGFBR1 mutations were more frequent among those with motor delays and feeding issues. CONCLUSIONS: Patients with LDS and/or their caregivers report at least one ND problem in most cases, and many require therapies. These data suggest ND disorders should be considered to be part of the phenotype.
Subject(s)
Language Development Disorders/therapy , Loeys-Dietz Syndrome , Motor Skills , Neurodevelopmental Disorders , Physical Therapy Modalities/statistics & numerical data , Receptor, Transforming Growth Factor-beta Type I/genetics , Adolescent , Child , Child Development , Feeding Behavior/physiology , Female , Humans , Loeys-Dietz Syndrome/epidemiology , Loeys-Dietz Syndrome/physiopathology , Loeys-Dietz Syndrome/psychology , Male , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/therapy , Prospective Studies , Speech Therapy/statistics & numerical data , United StatesABSTRACT
SATB2-associated syndrome (SAS) is a rare disorder caused by alterations in the special AT-rich sequence-binding protein 2 (SATB2). Skeletal abnormalities such as tibial bowing, osteomalacia, osteopenia or osteoporosis have been reported suggesting a higher frequency of skeletal complications in SAS. The optimal timing, necessity, and methodology for routine assessment of bone health in individuals with SAS, however, remain unclear. We report molecular and phenotypic features of 7 individuals with SAS documented to have low bone mineral density (BMD) ascertained by dual-energy X-ray absorptiometry (DXA), often preceded by tibial bowing. The lowest BMD Z-scores ranged -2.3 to -5.6. In 4 individuals, total alkaline phosphatase levels were elevated (2 with elevated bone fraction) around the time of low BMD documentation. A clinically significant fracture history and a diagnosis of pediatric osteoporosis were present in 4 individuals. Pamidronate treatment in 2 children improved BMD. In conclusion, low BMD, fractures, and tibial bowing are relatively common skeletal complications in individuals with SAS. DXA is a useful tool when evaluating a child with SAS suspected to have low BMD and the results might alter clinical management.
Subject(s)
Bone Development/genetics , Bone Diseases, Developmental/diagnosis , Bone Diseases, Developmental/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/genetics , Adolescent , Bone Density , Bone and Bones/diagnostic imaging , Bone and Bones/metabolism , Child , Child, Preschool , Female , Humans , Male , Phenotype , Radiography , SyndromeABSTRACT
SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.
Subject(s)
Craniofacial Abnormalities/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/genetics , Adolescent , Child , Child, Preschool , Craniofacial Abnormalities/physiopathology , Developmental Disabilities/physiopathology , Exome/genetics , Female , Frameshift Mutation , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Infant , Intellectual Disability/physiopathology , Male , PhenotypeSubject(s)
Congenital Abnormalities/genetics , Mutation, Missense , Sodium Channels/genetics , Adolescent , Cerebellum/abnormalities , Child, Preschool , Congenital Abnormalities/metabolism , Contracture/genetics , Contracture/metabolism , DNA Mutational Analysis , Female , Humans , Infant , Intellectual Disability/genetics , Intellectual Disability/metabolism , Ion Channels , Male , Membrane Proteins , Syndrome , Exome SequencingABSTRACT
We present a case of a 9-month-old Hispanic female with Kabuki syndrome with some infrequent manifestations including a single umbilical artery, butterfly vertebrae, a small larynx, a preauricular pit, microtia with internal ear abnormalities, abnormal calcium metabolism, premature thelarche, neonatal/persistent hypoglycemia and eventration of the diaphragm. She was found to have a previously unreported nonsense MLL2 mutation. This is the first case that includes all such findings occurring simultaneously that was genotyped.
