Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial.

BACKGROUND/AIMS: To assess auxological and safety data for growth hormone (GH)-treated children with SHOX deficiency. METHODS: Data were examined for GH-treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. RESULTS: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified. CONCLUSION: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns.

Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population.

BACKGROUND: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation. METHODS: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis. RESULTS: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications. CONCLUSIONS: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.

Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study.

CONTEXT: Previous studies showed improvement in impaired quality of life (QoL) in adult patients with growth hormone (GH) deficiency (GHD) who were treated with GH; improvement was sustained over a few years after GH therapy. OBJECTIVE: To evaluate the QoL over 10 years. DESIGN: This was a prospective observational study. SETTING: The study was conducted in clinical practice. PATIENTS: 1436 adult patients with adult-onset (AO) GHD (mean age [standard deviation (SD)]: 49.0 [12.2] years; 49% female) and 96 with childhood-onset (CO) GHD (31.3 [10.0] years; 60% female) (total N = 1532). INTERVENTION: GH therapy. MAIN OUTCOME MEASURES: QoL was measured by Questions on Life Satisfaction-Hypopituitarism (QLS-H) in countries where validated questionnaires and normative data for calculation of Z-scores were available. Change in QoL was tested by Student's t test and predicted by mixed-model repeated measures (MMRM) analysis. RESULTS: At study entry, patients had diminished QoL Z-scores (mean [SD] AO, -1.55 [1.69]; CO -0.98 [1.32]). The largest QoL improvements were in the first year: mean (SD) increase 0.77 (1.37) for AO (P < .001) and 0.50 (1.37) for CO (P < .001). The initial improvement from study entry remained statistically significant throughout 10 years for AO and in years 1 to 4, 6, and 7 for CO (P < .05). MMRM analysis predicted a greater QoL improvement in those who were not depressed, lived in Europe, had poorer Z-scores at entry, had lower body mass index at entry, and had no impaired vision. CONCLUSION: These data suggest that GH replacement provides sustained improvement in QLS-H scores toward normality for up to 10 years.

Genotypes and phenotypes of children with SHOX deficiency in France.

CONTEXT: The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified. OBJECTIVES: The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France. DESIGN, SETTING, AND PATIENTS: Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS). INTERVENTION AND MAIN OUTCOME MEASURE: SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D). RESULTS: Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies. CONCLUSIONS: SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.

Clinical and radiological characteristics of 22 children with SHOX anomalies and familial short stature suggestive of Léri-Weill Dyschondrosteosis.

AIMS: To describe genetic, clinical, anthropometric and radiological characteristics of 22 children with SHOX gene anomalies and familial short stature suggestive of Léri-Weill dyschondrosteosis. METHODS: Monocentric retrospective observational study. RESULTS: Six children (27%) presented with deletions located downstream of SHOX (mean height -1.4 ± 0.9 SDS) and 16 (68%) with either deletions encompassing SHOX, intragenic deletions or point mutations of SHOX (mean patient height for the 3 latter types of anomalies: -2.6 ± 0.8 SDS). In our sample, the two most frequently observed dysmorphic signs were clinical and/or radiological Madelung deformity (86%) and high arched palate (77%). Half the girls were born small for gestational age. Sixteen children treated with recombinant growth hormone had an increase in height from -2.7 ± 0.7 to -1.4 ± 0.7 SDS. Four children achieved adult height (-2.0 ± 0.9 SDS) with a gain over baseline height of 1.0 ± 0.5 SDS after a mean treatment duration of 5.8 ± 2.1 years. CONCLUSION: Patients shared common clinical, anthropometric and radiological signs but their height deficit varied, depending on the type of the SHOX gene anomaly. Due to the small size of our sample, our findings need to be confirmed in a larger population of patients.

Long-term improvement of quality of life during growth hormone (GH) replacement therapy in adults with GH deficiency, as measured by questions on life satisfaction-hypopituitarism (QLS-H).

Questions on Life Satisfaction-Hypopituitarism (QLS-H) is a new quality-of-life (QoL) questionnaire developed for adults with hypopituitarism. To determine the effects of long-term GH treatment on QoL, we evaluated QLS-H Z-scores in 576 adult patients with GH deficiency (GHD) enrolled in HypoCCS, an international observational study, using data from five countries in which comparative QLS-H data from the general population were available. Baseline QLS-H Z-scores were significantly lower in GH-deficient patients than in the general population of the same age, gender, and nationality. Z-scores were also significantly lower in female patients vs. males (P = 0.006) and in adult-onset vs. childhood-onset GHD (P = 0.002). Multivariate analysis associated female gender, multiple pituitary hormone deficiencies, low serum IGF-I values (<75 micro g/liter), and concomitant antidepressant medication with low baseline Z-scores. QLS-H Z-scores increased from -1.02 +/- 1.43 (SD) at baseline to -0.25 +/- 1.34 (SD) after 1 yr of GH treatment (P < 0.001) and were no longer significantly different from the general population after 4 yr of treatment. There was no correlation between change in Z-score and GH dose or changes in IGF-I and IGF binding protein-3 during treatment. This study demonstrates that 1) improvements in QoL, as measured by the QLS-H, are maintained during long-term GH replacement therapy of adults with GHD, and 2) the QLS-H is a useful tool for evaluating QoL in hypopituitary patients treated in clinical practice. The authors suggest that evaluation of QoL should be a part of the routine clinical management of adult GH-deficient patients, complementing the measurement of surrogate biological markers or other clinical end points.

Decreased quality of life in adult patients with growth hormone deficiency compared with general populations using the new, validated, self-weighted questionnaire, questions on life satisfaction hypopituitarism module.

To develop reference ranges for the Questions on Life Satisfaction Hypopituitarism Module (QLS-H), a new quality of life questionnaire for patients with hypopituitarism, data from 8177 adults were collected in France, Germany, Italy, The Netherlands, Spain, the United Kingdom, and the United States QLS-H scores declined with age, were lower in females than males, and differed significantly among countries. From these reference ranges we derived equations for z-scores, which adjust for age, gender, and country. QLS-H results from 957 adults with GH deficiency (GHD) participating in clinical trials were analyzed. At baseline, QLS-H scores were lower in females and differed significantly among countries. QLS-H scores significantly increased after GH treatment (6-8 months), but differences by country persisted. Calculating z-scores for patients eliminated all gender and most country differences. Pooled z-scores (mean +/- SD) from all patients increased from -0.99 +/- 1.39 at baseline to -0.14 +/- 1.30 after GH treatment. Quality of life assessment in adults with GHD requires the use of z-scores to correct for age, gender, and country differences. This approach allows pooling of data from different cohorts and comparison with general populations. QLS-H scores in adults with GHD were significantly decreased at baseline and were almost normalized after 6-8 months of GH therapy.