Atypical X-linked SCID phenotype associated with growth hormone hyporesponsiveness

Severe combined immunodeficiency (SCID) is a heterogeneous group of disorders characterized by defect of T- and B-cell immunity. In many cases of autosomal recessive SCID, thus far described, the molecular alteration involves genes encoding for molecules that participate in the signal transduction. We report on a patient affected by a combined immunodeficiency, characterized by severe T-cell functional impairment, in spite of a close to normal number of circulating mature type T and B cells. NK cells were absent. Associated with the immunodeficiency, this patient also showed short stature characterized by very low growth velocity, delayed bone age and absence of increase of the plasma levels of Insulin growth factor-I (IGF-I) after growth hormone (GH) in vivo stimulation indicating peripheral hyporesponsiveness to GH. Evaluation of the protein tyrosine phosphorylation events occurring following either T-cell receptor (TCR) or GH receptor (GHR) triggering revealed striking abnormalities. No molecular alteration of GHR gene was found, thus suggesting the presence of postreceptorial blockage. Mutational screening and expression analysis failed to reveal any molecular alteration of JAK2 and STAT 5 A/B genes thus ruling out the involvement of these genes in the pathogenesis of this form of SCID. Mutational analysis of IL2Rgamma chain gene revealed the presence of a L183S missense mutation, thus indicating an atypical and a more complex clinical presentation of this X-linked form of SCID. At our knowledge, this is the first report on the GH hyporesponsiveness in this disease.