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Periventricular nodular heterotopia (PVNH1; MIM 300049), otopalatodigital syndrome, type I (OPD1; MIM 311300), otopalatodigital syndrome, type II (OPD2; MIM 304120), frontometaphyseal dysplasia (FMD; 305620), Melnick-Needles syndrome (MNS; MIM 309350), cardiac valvular dysplasia, X-linked (CVD1; MIM 314400), and terminal osseous dysplasia (TOD; MIM 300244) are X-linked disorders caused by mutations in the gene encoding filamin A, FLNA. Filamin A is a phosphoprotein involved in cross-linking of the cytoskeleton actin filaments and in anchoring membrane proteins to the actin cytoskeleton.  Filamin A is known to bind at least 45 different proteins and has been implicated in the regulation of cellular signaling pathways.

PVNH1 is a neuronal migration disorder characterized by multiple noncalcified nodules consisting of differentiated neurons located in the cerebral periventricular region.  Many, but not all females with the disorder suffer seizures that are refractory to treatment.  Many patients with PVNH1 have connective tissue abnormalities such as joint hypermobility and dislocations, and aortic dilation. Additional findings may include cardiac valve abnormalities, coronary artery aneurysms, soft, velvety hyperextensible skin with easy bruising and atrophic scars, pectus excavatum, hernia and scoliosis/lordosis, hemoptysis/pulmonary hemorrhage and emphysema. PVNH1 is usually caused by loss of function mutations in FLNA.  Males with loss of function FLNA mutations die in utero or shortly after birth.  Surviving males with PVNH1 are either somatic mosaics or seemingly have FLNA missense mutations that do not lead to complete loss of function.  Additional findings in females with PVNH1 may include patent ductus arteriosus, coagulopathy with associated strokes, mild mental retardation, and gut dysmotility.

The otopalatodigital syndrome group consists of OPD1, OPD2, FMD and MNS.  These disorders may represent a phenotypic continuum and are characterized by a skeletal dysplasia and combinations of craniofacial, genitourinary, cardiac, intestinal and brain anomalies. They are caused by missense mutations or small in-frame deletions in FLNA. In contrast to that observed in PVNH1, FLNA mutations in the otopalatodigital syndromes typically result in a gain of function.
         Males with OPD1 may have cleft palate, short stature with mild skeletal abnormalities including absent frontal or sphenoid sinuses, prominent occiput and supraorbital ridges, thick skull base and frontal bones, delayed closure of the anterior fontanel, small pedicles, small iliac crests, numerous abnormalities of the limbs, hands and feet, pectus excavatum, and conductive hearing loss due to dense middle ear ossicles.  OPD1 represents the mild end of the phenotypic spectrum. There is full penetrance in males and variable expressivity in females.
        FMD shares many features with OPD1.  It is a skeletal dysplasia characterized by supraorbital hyperostosis, abnormalities of the tubular bones including an Erlenmeyer-flask appearance of the femur and tibia and increased diaphyseal bone density. Patients may have mitral valve prolapse, atrial and ventricular septal defects, vascular aneurysms, subglottic tracheal narrowing and genitourinary anomalies including hydronephrosis and hydroureter. Muscular hypotonia is also a common feature. Mental retardation may also be present. Perinatal death may occur in males and obligate female carriers may be affected.
      OPD2 is a more serious disorder. Many patients are stillborn or die within a few months of birth.  Males with OPD2 have disabling skeletal abnormalities including hypoplasia of the thorax, bowed long bones and undermineralized calvarium. In contrast to OPD1, malformations of the central nervous system including hydrocephalus and cerebellar hypoplasia are observed. Septal and right ventricular outflow tract defects, omphalocoele, hydronephrosis and hypospadias occur. Obligate female carriers display mild skeletal features and may rarely present with more serious manifestations.
      MNS displays the most severe phenotype of the four otopalatodigital syndromes. It is characterized by a skeletal dysplasia in the heterozygote (affected females). Males of affected females are stillborn or die in the perinatal period. Affected males exhibit severe phenotypes similar to that seen in OPD2. These males may have exopthalmus, omphalocele, thin calvaria, curved long bones, and hypoplastic or absent thumbs and halluces. Affected females with Melnick-Needles syndrome have a skeletal dysplasia characterized by undermineralization of the calvarium, sclerosis of the skull base, campomelia, cortical irregularities with bowing of the long bones and metaphyseal flaring.  Rib abnormalities lead to thoracic restriction. Other findings include undermodeling of the metacarpals, metatarsals and phalanges, sensorineural deafness, hydronephrosis and ureteral stenosis. Cardiac defects are rarely detected.
    
CVD1 is a non-syndromic disorder characterized by myxomatous dystrophy of the cardiac valves. FLNA mutations have recently been described in this disorder. The mitral and aortic valves are most often affected but any heart valve may display a valvulopathy.  Valvular manifestations include myxoid dystrophy with thickening of valve leaflets, regurgitation and prolapse. Males with FLNA mutations are clinically affected (complete penetrance) but females are often asymptomatic. Ultrasound studies have revealed that some female carriers are clinically affected (incomplete penetrance with variable degrees of expression). The findings in females are consistent with different X-inactivation patterns.

TOD is an X-linked dominant male-lethal disease characterized by distal skeletal dysplasia of the limbs, pigmentary defects of the skin and digital fibroma. The skeletal findings include abnormal and delayed ossification of bones in the hands and feet, leading to brachydactyly, camptodactyly, and clinodactyly, severe limb deformities, and joint contractures. Additional findings may include iris colobomas, midface hypoplasia, cardiac and urogenital malformations. Thus far, one recurrent mutation has been reported in TOD.