ABSTRACT
Three siblings are described with a distinct phenotype characterized by dysmorphic facial features, profound hypotonia, seizures and precocious puberty. No cause has been identified in spite of numerous investigations, including array-comparative genomic hybridization at a resolution of 1 Mb. Autosomal recessive inheritance is a possibility given that three siblings of both sexes are affected.
Subject(s)
Abnormalities, Multiple/pathology , Craniofacial Abnormalities/pathology , Epilepsy/pathology , Muscle Hypotonia/pathology , Puberty, Precocious/pathology , Abnormalities, Multiple/genetics , Child , Child, Preschool , Craniofacial Abnormalities/genetics , Epilepsy/genetics , Family Health , Fatal Outcome , Female , Genes, Recessive , Genomics , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Magnetic Resonance Imaging , Male , Muscle Hypotonia/genetics , Phenotype , Puberty, Precocious/geneticsABSTRACT
We describe two male siblings affected by cardiomyopathy and genitourinary tract abnormalities. One of them also had dysgenesis of the corpus callosum. They were born to nonconsanguineous, phenotypically normal parents. This association appears to be a new entity and may suggest a new autosomal or X-linked recessive syndrome.
Subject(s)
Cardiomyopathies/pathology , Chromosome Disorders/pathology , Genes, Recessive , Nervous System Malformations/pathology , Urogenital Abnormalities/pathology , Adult , Agenesis of Corpus Callosum , Cardiomyopathies/genetics , Chromosome Disorders/genetics , Female , Genes, X-Linked , Humans , Infant, Newborn , Kidney/abnormalities , Male , Nervous System Malformations/genetics , Siblings , Syndrome , Urogenital Abnormalities/geneticsABSTRACT
BACKGROUND: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. METHODS: Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. RESULTS AND DISCUSSION: The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.