Growth represents a multifactorial trait influenced by environmental and genetic factors. A new locus involved in linear growth has been implicated within the pseudoautosomal region (PAR) of the human sex chromosomes. Deletions encompassing this novel homeobox gene PHOG/SHOX have been shown to cause growth failure in idiopathic short stature and Turner syndrome. Investigators have estimated that 1.1% of all patients with idiopathic short stature may carry a SHOX mutation. (Nature Genetics 16:54-63, 1997) We report a patient with this defect who had a robust growth response to pharmacologic doses growth hormone. He was the 2.2 Kg product of a term uneventful pregnancy. The family history is unremarkable. Maternal height 153cm, paternal height 165 cm. His physical examination at 8 7/12 years of age revealed an unstigmatized prepubertal male with normal intelligence, height of 106.4 cm(height age 4 5/12 years) (height SDS -5 SD) weight 19.5 Kg, bone age 3 6/12 years, and a growth velocity of 2.8 cm/year. His endocrine evaluation revealed a peak growth hormone level of 30.8 ng/ml (nl > 10 ng/dl), IGF-1 of 193 ng/ml (nl 158-385 ng/ml), IGF binding protein- 3 of 2.2 mg/l (nl 1.5-3.4 mg/l), and a growth hormone binding protein of 854 pmol/L (nl 267-1638 pmol/L). A peripheral leukocyte culture revealed an unbalanced Y/13 translocation and FISH analysis indicated that the derivative chromosome contained the alpha satellite region and part of the short arm of the Y.Molecular analysis revealed no deletions up to the PAR boundary but dosage Southern blot analysis using cDNA probes indicated that the most of the PAR was lost, including PHOG/SHOX. The patient was begun on daily recombinant growth hormone treatment. His growth velocity improved to 9.4 cm/year (IGF-I level 260 ng/ml), during his first year and 7.4 cm/year during his second year of treatment (height SDS -3.03). We conclude that haploinsufficiency of PHOG/SHOX is responsible for the growth failure in our patient. Identification of patients with SHOX defects may help predict which children with idiopathic short stature will respond to the treatment.