Variability in anterior pituitary size within members of a family with GH deficiency due to a new splice mutation in the GHRH receptor gene

Summary objective Mutations in the GHRH receptor (GHRHR) gene (GHRHR) cause autosomal recessive isolated GH deficiency (IGHD), and are usually associated with anterior pituitary hypoplasia (APH) (defined as pituitary height more than 2 SDS below normal). We searched for GHRHR mutations and studied pituitary morphology in three prepubertal sibs with severe IGHD, who were born from consanguineous parents. design We sequenced the 13 exons and the intron–exon boundaries of the GHRHR of the index patient. After identifying a novel mutation, we sequenced the same area in the other family members. In addition, we performed magnetic resonance imaging (MRI) study of the pituitary (at age 8, 4 and 3 years) in the three affected subjects. results The three children were homozygous for a new GHRHR mutation that alters the second base of the invariant 5′ splice site (GT) of intron 12 [IVS12 + 2T→A]. The parents and an unaffected sibling were heterozygous for the same change. MRI did not show frank APH (by height criteria) in any of the subjects: pituitary height was normal (5·6 mm, +1·8 SDS) in the oldest sibling, and it was low but not below 2 SDS by age‐adjusted criteria in the second (3 mm, −1·4 SDS), and third sibling (2·8 mm, −1·7 SDS). Calculated pituitary volume was below −2 SDS in the youngest patient. conclusions These data demonstrate that pituitary height may fall within 2 SDS from the norm in patients with severe IGHD due to a homozygous GHRHR mutation, and that pituitary size may vary within patients with identical mutations who belong to the same family.