Improving clinical diagnosis in SHOX deficiency: the importance of growth velocity.

BackgroundThe aim of this study was to estimate the prevalence of haploinsufficiency of short stature homeobox containing gene (SHOX) deficiency (SHOXD) in a population of short-statured children, and to analyze their phenotype and the performance of clinical scores.MethodsScreening for SHOXD was performed in 281 children with short stature by direct sequencing and multiplex ligation probe-dependent amplification. Subjects with SHOXD were compared with 117 matched short patients without SHOXD. We calculated the cutoff of growth velocity associated with the highest sensitivity and specificity as a screening test for SHOXD by receiver operating characteristic curves.ResultsThe prevalence of SHOXD was 6.8%. Subjects with SHOXD showed a lower growth velocity (P<0.05) and a higher prevalence of dysmorphic signs. The best cutoff for growth velocity was -1.5 standard deviation score (SDS) both in the whole population and in subjects with a Rappold score <7 and <4 points. Growth velocity was ≤-1.5 SDS or Rappold score was >7/>4 points in 17/17 of 19 children with SHOXD and in 49/65 of 117 subjects without SHOX mutations.ConclusionsGrowth rate ≤-1.5 SDS, even with negative Rappold score, may be useful to detect precociously children with SHOXD. Selecting children deserving the genetic test by using growth velocity or the Rappold score significantly increases the sensitivity in detecting mutations and decreases the specificity.

SHOX deficiency in short Taiwanese children: A single-center experience.

BACKGROUND: SHOX deficiency is a common cause of idiopathic short stature. The aim of this study was to describe the clinical characteristics and molecular findings of patients with SHOX deficiency in Taiwan. METHODS: A phenotype scoring system was used to evaluate several anthropometric measures in patients with idiopathic short stature. Twenty-three patients with a phenotype score >7 were enrolled for SHOX gene analysis by MLPA and sequencing. Another patient with a deletion/insertion of the short arm of the X chromosome containing the SHOX gene was enrolled for the assessment. RESULTS: SHOX deficiency was detected in 26% of short children with a phenotype score >7. The arm-span-to-height ratio was significantly lower in SHOX-D patients than in non-SHOX-D patients. In patients with SHOX deficiency, an arm-span-to-height ratio <96.5% and short forearm were the most common characteristics. Three patients also exhibited typical radiological findings. A molecular analysis of the SHOX gene revealed five patients with intragenic deletions, one with a deletion in the regulatory region, and one with a missense mutation at exon 5. CONCLUSION: The phenotype scoring system is useful to select children with SHOX deficiency in Taiwan. Family history and radiological image of the radius are also of value for the diagnosis. This study may aid physicians in the early diagnosis of children with SHOX deficiency.

Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know.

PURPOSE OF REVIEW: This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options. RECENT FINDINGS: The use of multigene panels, using next-generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available.

Coexistence of dyschondrosteosis associated to SHOX deficiency, pseudohypoparathyroidism 1B, and chronic autoimmune thyroiditis: a case report.

We present an unusual case of SHOX deficiency associated with Léri-Weill dyschondrosteosis (LWD), Hashimoto's thyroiditis and pseudohypoparathyroidism 1B in a young woman. To our knowledge, this is the first ever report of these disorders coexisting. At the age of nine years, the proband was diagnosed of hypothyroidism due to Hashimoto's thyroiditis, and developed biochemical abnormalities consistent with hyperphosphatemia, mild hypocalcemia and elevated parathyroid hormone without any clinical symptoms except short stature. Replacement therapy with levothyroxine, calcium and alphacalcidol was initiated. The diagnosis of pseudohypoparathyroidism 1B was confirmed at the age of 17.5 years with the demonstration of methylation alteration at the GNAS locus. At the age of 16 years, 3.5 years after her menarche, she presented clear features of LWD. A large deletion of the SHOX gene was confirmed. Family genetic tests were not doable since she was adopted. We discuss the diagnostic challenges of these coexisting rare endocrinopathies.

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

Background Growth hormone (GH) treatment in children with short stature homeobox-containing gene (SHOX) deficiency is recognized to increase height velocity (HV) and adult height. Prediction of growth response continues to be a challenge. A comparatively accurate method is the Cologne prediction model developed in children with GH deficiency. The aim was to investigate whether this model also applies to patients with SHOX deficiency. Methods Included were 48 patients with SHOX deficiency confirmed by DNA analysis and treated with 0.05 mg/kg/day of somatropin. Prediction by the Cologne model uses the following variables: relative bone age (BA) retardation, baseline insulin-like growth factor-I (IGF-I), urinary deoxypyridinoline (DPD) cross-links at 4 weeks and HV at 3 months. Results HV and height standard deviation scores (SDS) increased significantly during the first year of treatment. Predicted and observed HV (cm/year) showed a Pearson correlation coefficient of 0.50 (p<0.001; root-mean-square error=1.63) and for first-year change in height SDS a Pearson correlation coefficient of 0.751 (p<0.001; root-mean-square error=0.32). Poor response could be adequately predicted using SDS change, with sensitivity and specificity both above 70% for certain thresholds. CONCLUSIONS: The results demonstrate that the Cologne model can be used to predict growth response in patients with SHOX deficiency with reasonable precision in the first treatment year, comparable to prediction in patients with GH deficiency.

A Track Record on SHOX: From Basic Research to Complex Models and Therapy.

SHOX deficiency is the most frequent genetic growth disorder associated with isolated and syndromic forms of short stature. Caused by mutations in the homeobox gene SHOX, its varied clinical manifestations include isolated short stature, Léri-Weill dyschondrosteosis, and Langer mesomelic dysplasia. In addition, SHOX deficiency contributes to the skeletal features in Turner syndrome. Causative SHOX mutations have allowed downstream pathology to be linked to defined molecular lesions. Expression levels of SHOX are tightly regulated, and almost half of the pathogenic mutations have affected enhancers. Clinical severity of SHOX deficiency varies between genders and ranges from normal stature to profound mesomelic skeletal dysplasia. Treatment options for children with SHOX deficiency are available. Two decades of research support the concept of SHOX as a transcription factor that integrates diverse aspects of bone development, growth plate biology, and apoptosis. Due to its absence in mouse, the animal models of choice have become chicken and zebrafish. These models, therefore, together with micromass cultures and primary cell lines, have been used to address SHOX function. Pathway and network analyses have identified interactors, target genes, and regulators. Here, we summarize recent data and give insight into the critical molecular and cellular functions of SHOX in the etiopathogenesis of short stature and limb development.

Growth and growth hormone: An overview.

Growth is a good indicator of a child's health. Growth disturbances, including short stature or growth failure, could be indications of illnesses such as chronic disease, nutritional deficits, celiac disease or hormonal abnormalities. Therefore, a careful assessment of the various requirements for normal growth needs to be done by history, physical examination, and screening laboratory tests. More details will be reviewed about the GH-IGF axis, its abnormalities with special emphasis on GH deficiency, its diagnosis and treatment. GH treatment indications in the US will be reviewed and a few only will be highlighted. They will include GH deficiency, as well as the treatment of children born SGA, including the results of a US study using FDA approved dose of 0.48mg/kg/week. GH deficiency in adults will also be briefly reviewed. Treatment of patients with SHOX deficiency will also be discussed. Possible side effects of GH treatment and the importance of monitoring safety will be highlighted.

Deformidad de Madelung: presentación de un caso / Madelung deformity: case report

La deformidad de Madelung es una alteración poco común de la articulación de las muñecas, con una prevalencia desconocida por los pocos casos reportados hasta la actualidad. Se vincula a mutaciones del gen SHOX. Se caracteriza por presentar alteraciones en el radio, el carpo y el cúbito, con predominio bilateral. Afecta principalmente a pacientes de sexo femenino; los signos y síntomas se revelan al inicio de la adolescencia. Presentamos el caso clínico de una paciente de sexo femenino de 17 años que registra las manifestaciones clínicas y radiográficas características. (AU)

Madelung deformity is a rare alteration of the wrist joint of unknown prevalence due to the few cases reported. It has been linked to SHOX gene mutations. Madelung deformity is characterized by alterations of the radius, carpus and ulna, predominantly bilateral and mainly seen in female patients at the beginning of the adolescence. We report the clinical case of a 17-yearold female patient presenting the characteristic clinical and radiographic deformities. (AU)