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Darya Gorbenko Del Blanco, Laura C G de Graaff, Dirk Posthouwer, Theo J Visser, and Anita C S Hokken-Koelega

Objective

In most patients, the genetic cause of isolated GH deficiency (IGHD) is unknown. By identifying several genes associated with height variability within the normal population, three separate genome-wide association studies provided new candidate genes for human growth disorders. We selected two of them for genetic screening of our IGHD population.

Aim

We aimed to determine whether high-mobility group A2 (HMGA2) and cyclin-dependent protein kinase 6 (CDK6) are involved in the pathogenicity of IGHD.

Methods

We directly sequenced coding regions and exon–intron boundaries of the genes HMGA2 and CDK6 in 105 Caucasian IGHD patients from the Dutch HYPOPIT study. In addition, we developed a new probe set of multiplex ligation-dependent probe amplification for both genes in order to detect copy number variations.

Results

In one patient with classical IGHD phenotype, we identified a new heterozygous 20 bp deletion in the intronic region of HMGA2 (c.250-29_-9del), which was absent in the databases and healthy controls. Together, with recently published data concerning the 12q14 microdeletion syndrome, where patients with an HMGA2 haploinsufficiency had proportionate short stature, this study provides further support of the important role for HMGA2 in growth. In CDK6, we found only known polymorphisms.

Conclusions

This study provides the first report of a deletion in the HMGA2 gene that might be related to IGHD. We suggest that this gene is investigated as a second screening in patients with a classical IGHD phenotype in which mutations in classical candidate genes have been excluded.

Free access

Darya Gorbenko Del Blanco, Christopher J Romero, Daniel Diaczok, Laura C G de Graaff, Sally Radovick, and Anita C S Hokken-Koelega

Orthodenticle homolog 2 (OTX2) is a homeobox family transcription factor required for brain and eye formation. Various genetic alterations in OTX2 have been described, mostly in patients with severe ocular malformations. In order to expand the knowledge of the spectrum of OTX2 mutation, we performed OTX2 mutation screening in 92 patients with combined pituitary hormone deficiency (CPHD). We directly sequenced the coding regions and exon–intron boundaries of OTX2 in 92 CPHD patients from the Dutch HYPOPIT study in whom mutations in the classical CPHD genes PROP1, POU1F1, HESX1, LHX3, and LHX4 had been ruled out. Among 92 CPHD patients, we identified a novel heterozygous missense mutation c.401C>G (p.Pro134Arg) in a patient with CPHD, pituitary malformation, and an underdeveloped left optic nerve. Binding of both the wild-type and mutant OTX2 proteins to bicoid binding sites was equivalent; however, the mutant OTX2 exhibited decreased transactivation. We describe a novel missense heterozygous OTX2 mutation that acts as a dominant negative inhibitor of target gene expression in a patient with CPHD, pituitary malformation, and optic nerve hypoplasia. We provide an overview of all OTX2 mutations described till date, which show that OTX2 is a promising candidate gene for genetic screening of patients with CPHD or isolated GH deficiency (IGHD). As the majority of the OTX2 mutations found in patients with CPHD, IGHD, or short stature have been found in exon 5, we recommend starting mutational screening in those patients in exon 5 of the gene.

Restricted access

Layla Damen, Lionne N. Grootjen, Stephany H. Donze, Laura C.g. de Graaff, Janielle A.e.m. van der Velden, and Anita Cs Hokken-Koelega

Objective:

In children with Prader-Willi syndrome (PWS), growth hormone (GH) treatment has positive effects on bone mineral density (BMD). Two one-year studies did not show a difference between GH or placebo on BMD in young adults with PWS. However, there are no studies investigating BMD during longer-term GH treatment in young adults with PWS.

Design:

Open-label, prospective study in 43 young adults with PWS.

Methods:

BMD of the total body (BMDTBSDS) and lumbar spine (BMADLSSDS) measured by DXA.

Results:

In the total group, estimated mean (95% CI) BMDTB remained similar during 3 years of GH, being -0.76 (-1.11 to -0.41) SDS at start and -0.90 (-1.27 to -0.54) SDS after 3 years (p=0.11), as did BMADLS, being -0.36 (-0.72 to 0.01) SDS and -0.46 (-0.77 to -0.16) SDS resp. (p=0.16). In men, there was a significant decrease in BMDTBSDS during 3 years of GH, while BMADLSSDS remained similar. In women, both BMDTBSDS and BMADLSSDS remained similar. BMDTBSDS was associated with female sex, lean body mass and age. The majority of patients received sex steroid replacement therapy (SSRT).

Conclusions:

During 3 years of combined GH and SSRT treatment, BMD remained stable in the normal range in young adults with PWS. However, men showed a decline in BMDTBSDS, probably due to insufficient SSRT. We recommend to continue GH treatment in young adults with PWS and to start SSRT during adolescence unless puberty progresses normally.