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Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co-existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify β-catenin activity. Mutations were identified in the FLNB gene (FLNB:p.F964L, FLNB:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated β-catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of β-catenin through the FLNB-MAP3K1-RAC1 complex by FLNB mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in SOX9 and gain-of-function mutations in MAP3K1.

Familial recurrence risks are poorly understood in cases of de novo mutations. In the event of parental germ line mosaicism, recurrence risks can be higher than generally appreciated, with implications for genetic counseling and clinical practice. In the course of treating a female with pubertal delay and hypergonadotropic hypogonadism, we identified a new missense mutation in the SRY gene, leading to somatic feminization of this karyotypically normal XY individual. We tested a younger sister despite a normal onset of puberty, who also possessed an XY karyotype and the same SRY mutation. Imaging studies in the sister revealed an ovarian tumor, which was removed. DNA from the father's blood possessed the wild type SRY sequence, and paternity testing was consistent with the given family structure. A brother was 46, XY with a wild type SRY sequence strongly suggesting paternal Y-chromosome germline mosaicism for the mutation. In disorders of sexual development (DSDs), early diagnosis is critical for optimal psychological development of the affected patients. In this case, preventive karyotypic screening allowed early diagnosis of a gonadal tumor in the sibling prior to the age of normal puberty. Our results suggest that cytological or molecular diagnosis should be applied for siblings of an affected DSD individual.

A girl of remarkably short stature, referred for investigation with the diagnosis of gonadal dysgenesis and the finding of a male karyotype, proved to be deficient in growth hormone and gonadotrophin secretion, and was treated with growth and sex hormones. It was concluded that this case demonstrates an apparently casual coincidence of pituitary insufficiency with XY gonadal dysgenesis, evidently the first to be reported.

46,XY gonadal dysgenesis was transmitted as an autosomal-dominant trait in a large family with multiple affected members. Expressivity of the trait was highly variable, ranging from pure to partial gonadal dysgenesis associated with normal female genitalia or sexual ambiguity, to mild hypospadias in otherwise normal males. The phenotypic features of this trait appeared to be confined to the genitourinary system. Multipoint parametric analysis using markers D5S664, D5S633, and D5D2102 yielded an LOD score of 4.47, assuming sex-limited, autosomal-dominant inheritance with a penetrance of 0.6. Because mutation in testis-determining genes leads to gonadal dysgenesis in 46,XY individuals, we postulate that the gene mapped by this study normally plays a role in gonadal differentiation.

A 23-year-old phenotypic female with congenital heart disease, mental retardation and mild virilization was referred for evaluation of short stature and delayed sexual development. Endocrine studies revealed a markedly elevated serum testosterone, which was within the adult range. At laparotomy, a small uterus, normal fallopian tubes and bilateral gonadal tumors, consisting of a left gonadoblastoma and right dysgerminoma were found. Trypsin G banding of peripheral blood revealed a 45,XO, 18p+ karyotype. Q banding demonstrated intense fluorescence of the distal portion of the extra material on chromosome 18, consistent with fluorescence of Y chromosomal heterochromatin. A combination of banding techniques enabled us to determine a 45,X,t(Y;18) (p11;p11) karyotype in peripheral blood. Cultures of gonadal tissue revealed 45,X,t(Y;18)/46,XY mosaicism.

We have studied two female newborns with camptomelic dwarfism, XY-gonadal dysgenesis and chromosome anomalies. The preponderance of “females” among the hitherto reported cases of this allegedly autosomal recessive form of lethal dwarfism may be due to an increased incidence of an associated XY-gonadal dysgenesis.