Loss-of-function of the immunoglobulin super family member 1 gene (IGSF1, OMIM#300888) causes an X-linked syndrome, characterized in males by congenital central hypothyroidism, delayed testosterone rise in puberty despite normal timing of testicular enlargement, adult macro-orchidism, and in some cases deficiencies of prolactin (PRL) and/or growth hormone (GH) (1,2,3).
In the present case, IGSF1 deficiency was diagnosed at the age of 19 years, based on a history of transient GH deficiency, persistent central hypothyroidism, and hypoprolactinemia, and the finding of macro-orchidism. The close follow-up during GH replacement, which was started one year before the onset of puberty, permitted a detailed recording of the genital and pubic hair development, pubertal growth spurt, and bone maturation.
The combination of persistent central hypothyroidism, transient partial GH deficiency, and macro-orchidism led to the suspicion of IGSF1 deficiency (1).
The main characteristics of this newly described genetic syndrome are congenital hypothyroidism of central origin and macro-orchidism. The diagnosis of central hypothyroidism is rarely made at birth as most neonatal screening programs for congenital hypothyroidism are based solely on the measurement of TSH.
Male children with an idiopathic combined GH and TSH deficiency, showing a persistent central hypothyroidism but a transient GH deficiency, should be screened for loss-of-function mutations or deletions of the IGSF1 gene, especially when delayed puberty and macro-orchidism are present.
Primary features of FRAXA are mild to severe mental retardation (2) (MR), macro-orchidism (3) associated with connective tissue disorder such as hyperextensible finger joints, double jointed thumbs, etc.
X-linked mental retardation, macro-orchidism, and the Xq27 fragile site.
These investigators demonstrated that by reducing mGluR5 protein expression by 50% in a mouse model of the disease, it was possible to bring all but one fragile X phenotype (macro-orchidism
) significantly closer to normal.