Growth response to growth hormone treatment in patients with SHOX deficiency can be predicted by the Cologne prediction model

Hoyer‐Kuhn, Heike; Franklin, Jeremy; Jones, Christine; Blum, Werner; Schöenau, Eckhard

doi:10.1515/jpem-2017-0282

Cited by 5 publications

(4 citation statements)

References 36 publications

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“…First, we have shown that approximately 1% of clubfoot probands have a microduplication of SHOX and that there is a significant enrichment of de novo duplications. Short stature homeobox ( SHOX ) is located in the PAR1 on the distal end of the short arms of the X and Y chromosomes, and encodes a homeodomain transcription factor expressed in the developing forelimb and lower leg, as well as the first and second pharyngeal arches 24 . SHOX escapes X-inactivation, hence XX and XY individuals both have two copies of SHOX 25 .…”

Section: Discussionmentioning

confidence: 99%

Rare andde novoduplications containingSHOXin clubfoot

et al. 2020

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IntroductionCongenital clubfoot is a common birth defect that affects at least 0.1% of all births. Nearly 25% cases are familial and the remaining are sporadic in inheritance. Copy number variants (CNVs) involving transcriptional regulators of limb development, including PITX1 and TBX4, have previously been shown to cause familial clubfoot, but much of the heritability remains unexplained.MethodsExome sequence data from 816 unrelated clubfoot cases and 2645 in-house controls were analysed using coverage data to identify rare CNVs. The precise size and location of duplications were then determined using high-density Affymetrix Cytoscan chromosomal microarray (CMA). Segregation in families and de novo status were determined using qantitative PCR.ResultsChromosome Xp22.33 duplications involving SHOX were identified in 1.1% of cases (9/816) compared with 0.07% of in-house controls (2/2645) (p=7.98×10−5, OR=14.57) and 0.27% (38/13592) of Atherosclerosis Risk in Communities/the Wellcome Trust Case Control Consortium 2 controls (p=0.001, OR=3.97). CMA validation confirmed an overlapping 180.28 kb duplicated region that included SHOX exons as well as downstream non-coding regions. In four of six sporadic cases where DNA was available for unaffected parents, the duplication was de novo. The probability of four de novo mutations in SHOX by chance in a cohort of 450 sporadic clubfoot cases is 5.4×10–10.ConclusionsMicroduplications of the pseudoautosomal chromosome Xp22.33 region (PAR1) containing SHOX and downstream enhancer elements occur in ~1% of patients with clubfoot. SHOX and regulatory regions have previously been implicated in skeletal dysplasia as well as idiopathic short stature, but have not yet been reported in clubfoot. SHOX duplications likely contribute to clubfoot pathogenesis by altering early limb development.

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Section: Discussionmentioning

confidence: 99%

Rare andde novoduplications containingSHOXin clubfoot

et al. 2020

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“…However, as the bone resorption marker is rarely measured, the model has only been used to a limited extent. However, the Cologne model was recently shown to effectively predict first year response to GH treatment in patients with short stature homeobox-containing gene ( SHOX ) deficiency ( 79 ).…”

Section: Prediction Modelsmentioning

confidence: 99%

Important Tools for Use by Pediatric Endocrinologists in the Assessment of Short Stature

Labarta¹,

Ranke²,

Maghnie³

et al. 2021

Jcrpe

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Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by using novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360° European Meeting on Growth and Endocrine Disorders, funded by Merck KGaA, Germany, and this review is based on those discussions. It was reported that electronic monitoring and new algorithms have been devised that are providing more sensitive referral for short stature. In addition, computer programs have improved ways in which diagnoses are coded for use by various groups including healthcare providers and government health systems. Innovative cranial imaging techniques have been devised that are considered safer than using gadolinium contrast agents and are also more sensitive and accurate. Deep-learning neural networks are changing the way that bone age and bone health are assessed, which are more objective than standard methodologies. Models for prediction of growth response to growth hormone (GH) treatment are being improved by applying novel artificial intelligence methods that can identify non-linear and linear factors that relate to response, providing more accurate predictions. Determination and interpretation of insulin-like growth factor-1 (IGF-1) levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-1 standard deviation score is among the most important indicators of GH therapy response. While physicians involved in child growth and treatment of disorders resulting in growth failure need to be aware of, and keep abreast of, these latest developments, treatment decisions and management should continue to be based on clinical decisions. New digital technologies and advancements in the field should be aimed at improving clinical decisions, making greater standardization of assessment and facilitating patient-centered approaches.

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“…A number of models have been devised to predict the growth response to GH therapy for various aetiologies (41,46,47,48,49,50,51). Using such models, the mean predicted height velocity with a standard dose of 0.3 mg/kg/week is approximately 2 cm/year greater for children with GH deficiency, compared with children born SGA and girls with Turner syndrome.…”

Section: Gh Therapy For Gh Deficiency and Non-gh Deficiency Causes Ofmentioning

confidence: 99%

Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy

Wit

Deeb

Bin-Abbas

et al. 2019

Jcrpe

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It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.

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Growth response to growth hormone treatment in patients with SHOX deficiency can be predicted by the Cologne prediction model

Cited by 5 publications

References 36 publications

Rare andde novoduplications containingSHOXin clubfoot

Rare andde novoduplications containingSHOXin clubfoot

Important Tools for Use by Pediatric Endocrinologists in the Assessment of Short Stature

Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy

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