Long-Term Results of GH Treatment in Silver-Russell Syndrome (SRS): Do They Benefit the Same as Non-SRS Short-SGA?

CONTEXT: Silver-Russell syndrome (SRS) is a genetically heterogeneous syndrome characterized by low birth weight, severe short stature, and variable dysmorphic features. GH treatment is a registered growth-promoting therapy for short children born small for gestational age, including SRS, but there are limited data on the GH response in SRS children and on differences in response among the (epi)genetic SRS subtypes (11p15 aberrations, maternal uniparental disomy of chromosome 7 [mUPD7], and idiopathic SRS). OBJECTIVES: To compare growth and adult height between GH-treated small for gestational age children with and without SRS (non-SRS), and to analyze the difference in GH response among SRS genotypes. DESIGN AND SETTING: A longitudinal study. PARTICIPANTS: Sixty-two SRS and 227 non-SRS subjects. INTERVENTION: All subjects received GH treatment (1 mg/m(2)/d). MAIN OUTCOME MEASURES: Adult height and total height gain. RESULTS: The SRS group consisted of 31 children with 11p15 aberrations, 11 children with mUPD7, and 20 children with idiopathic SRS. At the start of GH treatment, mean (SD) height standard deviation score [SDS] was significantly lower in SRS (-3.67 [1.0]) than in non-SRS (-2.92 [0.6]; P < .001). Adult height SDS was lower in SRS (-2.17 [0.8]) than in non-SRS (-1.65 [0.8]; P = .002), but the total height gain SDS was similar. There was a trend toward a greater height gain in mUPD7 than in 11p15 (P = .12). CONCLUSION: Children with SRS have a similar height gain during GH treatment as non-SRS subjects. All (epi)genetic SRS subtypes benefit from GH treatment, with a trend toward mUPD7 and idiopathic SRS having the greatest height gain.

The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects.

OBJECTIVE: Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers. DESIGN: In this retrospective multi-center study (2002-March 2014) clinical information was available from 130 patients (72 SHI, 44 SED, and 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height (SH), arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity, and index of responsiveness). RESULTS: Patients with SEDs showed similar HtSDS to patients with SHI (-2.3 and -2.6, respectively, P=0.2), but they were less disproportionate (SH/height ratio SDS 2.0 vs 3.1 (P<0.01) and extremities/trunk ratio 2.57 vs 2.43 (P=0.03)). The 1st year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (n=3) was similar to the other groups. CONCLUSIONS: Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.

Individual growth curve models for assessing evidence-based referral criteria in growth monitoring.

The goal of this study is to assess whether a growth curve model approach will lead to a more precise detection of Turner sydnrome (TS) than conventional referral criteria for growth monitoring. The Jenss-Bayley growth curve model was used to describe the process of growth over time. A new screening rule is defined on the parameters of this growth curve model, parental height and gestational age. The rule is applied to longitudinal growth data of a group of children with TS (n=777) and a reference (n=487) group. The outcome measures are sensitivity, specificity and median referral age. Growth curve parameters for TS children were different from reference children and can therefore be used for screening. The Jenss-Bayley growth model, which uses all longitudinal measurements from birth to a maximum age of 5 years with at least one measurement after the age of 2, together with parental height and gestational age can achieve a sensitivity of 85.2 per cent with a specificity of 99.5 per cent and a median referral age of 4.2 (the last measurement between the age of 2 and 5 of each child is considered to be the moment of referral). Sensitivity increases by 2 percentage points when decreasing the specificity to 99 per cent. The Jenss-Bayley growth model from birth to a maximum age of 8 years with at least one measurement after the age of 2, together with parental height results in a sensitivity of 89.0 per cent with a specificity of 99.5 per cent and a median referral age of 6.1. For a specificity of 98 per cent, we obtain a sensitivity of 92.3 per cent. In comparison to conventional rules applied to the same data, sensitivity is about 11-30 percentage points higher at the same level of specificity for the Jenss-Bayley growth rule. We conclude that from the age of 4, growth curve models can improve the screening on TS to conventional screening rules.

Towards evidence based referral criteria for growth monitoring.

AIMS: To evaluate the performance of growth monitoring in detecting diseases. Turner's syndrome (TS) is taken as the target disease. METHODS: Case-control simulation study. Three archetypal screening rules are applied to longitudinal growth data comparing a group with TS versus a reference group from birth to the age of 10 years. Main outcome measures were sensitivity, specificity, and median referral age. RESULTS: Clear differences in performance of the rules were found. The best rule takes parental height into account. Combining rules could improve diagnostic accuracy. CONCLUSION: Growth monitoring is useful to screen for TS. A combined rule that takes absolute height SDS, parental height, and deflection in height velocity into account is the best way to do this. Similar research is needed for other diseases, populations, and ages, and the results should be synthesised into evidence based referral criteria.