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.


METHODS
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.
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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Donze
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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Meijer
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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Kant
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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Zandwijken
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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van der Hout
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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van Spaendonk
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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van den Ouweland
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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JM
Wit
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
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Losekoot
Departments of PediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsDutch Growth Research Foundation ('Stichting Kind en Groei')PO Box 23068, 3001 KB Rotterdam, The NetherlandsDepartment of GeneticsUniversity Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The NetherlandsDepartment of Clinical GeneticsVU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The NetherlandsDepartment of Clinical GeneticsErasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands w.oostdijk@lumc.nl.
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Oostdijk
D000293:Adolescent; D001827:Body Height / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D006130:Growth Disorders / Q000188:drug therapy* / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D000074122:Short Stature Homeobox Protein; D016896:Treatment Outcome
D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D019382:Human Growth Hormone