Context: A variant of the human GH receptor (GHR) lacks a 22-amino-acid sequence derived from exon 3 (d3-GHR). It was reported that pediatric patients, born small for gestational age or with idiopathic short stature who were homozygous or heterozygous for this variant responded better to GH treatment than those homozygous for the full-length allele (fl-GHR). Objective:The objective was to study the impact of the GHR genotype on the phenotype and growth response in patients with isolated GH deficiency (IGHD) treated with GH.Design: This was a retrospective, multinational, multicenter observational study. Patients:Patients with IGHD (n ϭ 107) were recruited.Interventions: All patients received GH treatment at replacement doses. The GHR genotype (fl-GHR/fl-GHR, fl-GHR/d3-GHR, or d3-GHR/d3-GHR) was determined by PCR amplification. Main Outcome Measures:Measures included height SD score, height velocity, height velocity SD score at baseline and 1 yr of GH treatment, and their changes.Results: There was no statistically significant difference of the main outcome measures between patients with the d3-GHR allele (n ϭ 48) and patients who were homozygous for the fl-GHR allele (n ϭ 59). Moreover, the genotype group did not contribute significantly to the growth prediction in multiple linear regression models. Conclusions:Our results indicate that the d3-GHR allele does not affect response to GH treatment or contribute to growth predictions in patients with IGHD who received replacement doses of GH aiming to restore a normal GH status. We did not confirm the previously reported data obtained in patients small for gestational age or with idiopathic short stature who received supraphysiological GH doses.

LHX3 mutations are a rare cause of CPHD involving deficiencies for GH, prolactin, TSH, and LH/FSH in all patients. Whereas most patients have a severe hormone deficiency manifesting after birth, milder forms can be observed, and limited neck rotation is not a universal feature of patients with LHX3 mutations. This study extends the known molecular defects and range of phenotypes found in LHX3-associated diseases.

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Context: Cutoff limits of GH stimulation tests to diagnose GH deficiency (GHD) in children and adolescents are not sufficiently validated by clinical studies due to discrepancies in the performance of GH immunoassays and lack of available study populations. Objective: We aimed to establish new cutoff limits for GH stimulation tests based on clinical evidence and compared these immunoassay-based values with an antibody-independent mass spectrometric method. Design and setting: In a retrospective study, GH cutoff limits for eight different immunoassays and isotope dilution mass spectrometry (ID-MS) were calculated from hGH peak concentrations of short-statured children with and without GHD. Patients: We compared the serum GH peak concentrations at GH stimulation test of 52 short-statured children and adolescents, who have normal GH secretion at initial workup and normal growth in the follow-up, with the serum GH peak concentrations of 44 GHD patients in the same age range, in order to optimize the cutoff limit calculation. Results: Discriminant analysis of re-measured GH led to a new cutoff limit of 7.09 mg/l using the iSYS assay (IDS) and the limits for the other seven hGH assays varied between 4.32 and 7.77 mg/l. For ID-MS, cutoffs of 5.48 mg/l (22k GH) and 7.43 mg/l (total GH) were ascertained. Conclusion: The establishment of method-specific clinical evidence-based GH cutoff limits is of importance to ensure adequate clinical diagnosis and treatment of children and adolescents with GHD. ID-MS may become an important tool for providing both reliable and sustainable SI traceability of GH measurements in the future.

Context:The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency.Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. Design:The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. Patients:A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. Results:In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. A fter early inductive events, the development of the specialized hormone-secreting cells of the anterior pituitary gland is dependent on the actions of multiple transcription factors such as LHX3, LHX4, PIT1 (POU1F1 gene), PROP1, PITX1, PITX2, SF1, and TPIT (1). Of these, the structurally related LHX3 and LHX4 proteins are members of the LIMhomeodomain (HD) family of transcription factors (2). LIM-HD proteins feature two amino-terminal LIM domains, required for Conclusions