Genetic factors play a crucial role in determining human height. Short stature commonly affects multiple family members and therefore, familial short stature (FSS) represents a significant proportion of growth disorders. Traditionally, FSS was considered a benign polygenic condition representing a subcategory of idiopathic short stature (ISS). However, advancements in genetic research have revealed that FSS can also be monogenic, inherited in an autosomal dominant manner and can result from different mechanisms including primary growth plate disorders, growth hormone deficiency/insensitivity or by the disruption of fundamental intracellular pathways. These discoveries have highlighted a broader phenotypic spectrum for monogenic forms of short stature, which may exhibit mild manifestations indistinguishable from ISS. Given the overlapping features and the difficulty in differentiating polygenic from monogenic FSS without genetic testing, some researchers redefine FSS as a descriptive term that encompasses any familial occurrence of short stature, regardless of the underlying cause. This shift emphasizes the complexity of diagnosing and managing short stature within families, reflecting the diverse genetic landscape that influences human growth.

• Klíčová slova
• autosomal dominant short stature, familial short stature, genetics, growth plate, short stature,
• MeSH
• fenotyp MeSH
• lidé MeSH
• nanismus genetika   MeSH
• poruchy růstu * genetika   MeSH
• tělesná výška * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was -3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

• Klíčová slova
• combined pituitary hormone deficiency, genetics of short stature, growth hormone deficiency, next-generation sequencing, short stature,
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• endocrinological diseases, genetics, growth hormone, short stature, stimulation tests,
• MeSH
• lidé MeSH
• lidský růstový hormon * terapeutické užití   MeSH
• nanismus * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• úvodníky MeSH
• Názvy látek
• lidský růstový hormon * MeSH

Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader-Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH-insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent's height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent's heights ≤-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent's height and BA are clinical predictors of monogenic FSS.

• Klíčová slova
• GH treatment, familial short stature, growth plate disorders, next-generation sequencing, predictors of monogenic short stature,
• Publikační typ
• časopisecké články MeSH