Short stature

Short stature encompasses a clinically heterogeneous spectrum, ranging from isolated growth failure to syndromic disorders with multisystem involvement. Isolated, nonsyndromic forms are identified through deviation from age- and sex-matched growth curves alone, whereas syndromic forms accompany dysmorphic features, developmental delay, or other organ involvement and substantially raise the prior probability of an identifiable monogenic or chromosomal cause. Severe short stature, conventionally a height standard-deviation score at or below -3, and clinical disproportion on examination are recognised criteria for prioritising genetic evaluation. The age of onset varies depending on the underlying etiology, with some conditions manifesting prenatally or at birth, while others become apparent during early childhood or around the pubertal growth spurt.

The estimated prevalence of short stature varies depending on the height cutoff, study population, and geographic region. For example, a population-based study in England of 7,062,071 children aged 4-5 years reported an estimated prevalence of 1.93% (95% CI 1.92-1.94).

Short stature can result from a wide range of genetic abnormalities that interfere with normal growth plate development and endochondral bone formation. These defects involve multiple molecular mechanisms, including disturbances in intracellular signaling pathways, transcriptional regulation, extracellular matrix organization, paracrine signaling, and the growth hormone-IGF-1 axis. Variants in genes such as FGFR3, SHOX, NPR2, GHR, and components of the RAS-MAPK pathway can impair chondrocyte proliferation, differentiation and maturation, leading to both syndromic and isolated forms of short stature.

The genetic conditions associated with short stature follow heterogeneous inheritance patterns. The spectrum spans autosomal-dominant and autosomal-recessive monogenic disorders, X-linked conditions, chromosomal abnormalities, and imprinting-related primordial growth failure.

• Where short stature is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Orr J, Freer J, Morris JK, Hancock C, Walton R, Dunkel L, et al. Regional differences in short stature in England between 2006 and 2019: a cross-sectional analysis from the National Child Measurement Programme. PLoS Med. 2021;18(9). doi:10.1371/journal.pmed.1003760. PMID:; PMCID: PMC8478195
• van der Kaay DCM, Rochtus A, Binder G, Kurth I, Prawitt D, Netchine I, et al. Comprehensive genetic testing approaches as the basis for personalized management of growth disturbances: current status and perspectives. Endocr Connect. 2022;11(11). doi:10.1530/EC-22-0277. PMID:; PMCID: PMC9578069
• Rapaport R, Wit JM, Savage MO. Growth failure: “idiopathic” only after a detailed diagnostic evaluation. Endocr Connect. 2021;10(3). doi:10.1530/EC-20-0585. PMID:; PMCID: PMC8052574.