Short Stature of Genetic Cause – Diagnostic Approach

Clinical, auxological and genetic approach to the child with short stature: descriptive and aetiological classification, chromosomal, epigenetic and monogenic causes (growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis, growth plate, skeletal dysplasias, RASopathies, imprinting disorders, primordial dwarfism and syndromes), testing algorithm and indications for growth-promoting drugs.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Short stature as a clinical problem

Short stature is the most frequent reason for referral to paediatric endocrinology and a feature shared by hundreds of genetic syndromes [4, 60]. Human height is a quantitative trait with a heritability of about 80% in twin studies; genome-wide association studies have identified more than 12,000 independent common nucleotide variants, distributed across more than 7000 segments covering about 21% of the genome, each with an effect of less than 2 mm, which together explain about half of the heritability, to which rare variants with effects of 1 to 4 cm are added [1]. This architecture gives rise to the central clinical distinction: most short children have a normal variant of growth, of polygenic origin (familial short stature) or maturational origin (constitutional delay of growth and puberty), whereas a minority have a monogenic, chromosomal or epigenetic cause, or one secondary to systemic disease, whose identification changes prognosis, counselling and, sometimes, treatment [1, 4].

In a classic reference series, familial short stature and constitutional delay accounted for about 75% of the children assessed, chronic diseases 10%, syndromes 6%, chromosomal anomalies 5%, skeletal dysplasias 1% and growth hormone (GH) deficiency or insensitivity 1 to 2% [4]. These proportions describe populations referred before the genomic era and not a population prevalence; with next-generation sequencing, a growing fraction of children previously labelled as "idiopathic" receive a molecular diagnosis [1, 3].

1.2. Historical milestones

Treatment with human GH extracted from cadaveric pituitaries was described by Raben in 1958 in a patient with pituitary dwarfism [61]. Molecular characterisation of the GH–IGF axis began with Laron syndrome, an autosomal recessive disease with high GH and low insulin-like growth factor 1 (IGF-1): in 1989, Godowski and colleagues described the structure of the GH receptor gene (GHR), with nine coding exons spanning at least 87 kb of chromosome 5, and demonstrated deletions of the extracellular binding domain in 2 of 9 patients, the first direct evidence that GH insensitivity results from a structural defect of the receptor [62]. There followed the deletion of the IGF1 gene in 1996 [63], IGF1R variants with prenatal and postnatal growth restriction in 2003 [64], GH insensitivity due to STAT5B in 2003 [65], acid-labile subunit deficiency (IGFALS) in 2004 [66] and PAPPA2 deficiency, with raised total IGF-1 but low free IGF-1, in 2016 [67].

At the growth plate, Rao and colleagues delimited in 1997 a 170 kb interval in pseudoautosomal region 1 (PAR1), deleted in 36 short individuals with Xp22/Yp11.3 rearrangements, isolated the homeobox gene SHOX and identified a functional variant in 91 children with idiopathic short stature, linking the same gene to idiopathic short stature and to the short stature of Turner syndrome [68]. In the 2010s, exome sequencing revealed growth plate causes (ACAN, NPR2, IHH, FGFR3 in mild phenotypes) and evolutionarily conserved height gene networks, with multiple Mendelian causes of short stature [14, 69].

1.3. Nomenclature and reclassifications

The 2008 consensus defined idiopathic short stature (ISS) as height more than 2 SD below the mean for age, sex and population, without identifiable disease, subdivided into familial and non-familial and with or without pubertal delay, to be distinguished from dysmorphic syndromes, skeletal dysplasias, short stature after birth small for gestational age (SGA) and systemic and endocrine diseases [2]. The 2026 international guideline on genetic testing, initiated by the European Society for Paediatric Endocrinology (ESPE) and endorsed by paediatric endocrinology and human genetics societies from Europe, North and Latin America, China, Japan and Australasia, replaced this designation with "isolated idiopathic short stature" (normal birth size) and "isolated idiopathic short SGA", at the end of a descriptive classification into four categories: isolated short stature, suspected skeletal dysplasia, suspected GH/IGF-1 axis defect and syndromic short stature [1]. In parallel, an international Delphi consensus on ISS (44 statements with 77–100% agreement) kept the definition of height below −2 SD (2.3rd centile) without identifiable pathology and noted the absence of a dedicated ICD-11 code [70], and a Brazilian group proposed the designation "healthy short stature" for healthy children at the lower end of normal variation, arguing that each new aetiological discovery shrinks and destabilises the idiopathic category [3].

The Delphi consensus on ISS was built by a steering committee of 10 experts and voted on by a panel of 22 paediatric endocrinologists (North America 5, Europe 9, Brazil 1, China 2, Israel 2, Japan 3) in three rounds between November 2025 and February 2026, with a consensus threshold of 70%; 26 of 49 statements reached consensus in the first round and 18 of 18 in the second [70]. It was endorsed by the Chinese Society of Pediatric Endocrinology and Metabolism (CSPEM), by ESPE and by the Latin American Society for Pediatric Endocrinology (SLEP); the Pediatric Endocrine Society (PES) acknowledged its educational value, without endorsing it as a guideline [70]. The authors themselves stress that these are expert opinion recommendations, without a systematic review or grading of the evidence by the GRADE method (Grading of Recommendations, Assessment, Development and Evaluation), without representation from Africa or South Asia, and with funding from two manufacturers of long-acting somatropin, with no declared role in the design or writing [70]. The consensus expressly excludes from ISS children born SGA and those with constitutional delay of growth and puberty (CDGP), which it considers distinct aetiological groups [70].

The supplementary material of the 2026 guideline details the final aetiological classification [1]. Primary disorders (intrinsic to the growth plate) are divided into monogenic defects of intracellular pathways (SHOX deficiency, Noonan syndrome and other RASopathies, Bloom, Seckel spectrum, Albright hereditary osteodystrophy), of paracrine signalling (loss of function of NPR2 and IHH, gain of function of FGFR3, PTH1R variants), of the extracellular matrix (ACAN, type 2 collagenopathies, osteogenesis imperfecta) and of uncertain mechanism, and into chromosomal anomalies and multigenic CNVs (Turner, 45,X/46,XY mosaicism, trisomy 21, 22q11.2 microdeletion) [1]. Secondary disorders (extrinsic to the plate) are grouped into malnutrition, diseases of other organs (cardiac, pulmonary, hepatic, gastrointestinal, renal, chronic anaemia, neuromuscular, autoimmune), endocrine diseases (GH deficiency; GH insensitivity due to GHR, STAT5B or QSOX2; defects of IGF1, IGF2 and IGF1R; IGF-1 transport defects due to IGFALS and PAPPA2; CDGP and precocious puberty; hypothyroidism, including congenital non-goitrous hypothyroidism type 6 due to THRA; glucocorticoid excess), metabolic diseases (rickets, hypophosphatasia, disorders of carbohydrate, lipid and protein metabolism), psychosocial and iatrogenic causes [1]. The third group brings together short stature of unknown cause: isolated with normal birth size ("isolated idiopathic short stature", the former ISS), isolated with low birth size ("isolated idiopathic short SGA") and non-isolated without aetiology, with normal or low birth size [1].

1.4. Definitions used in this article

Short stature refers to any of three manifestations: height below −2.0 SD; a decrease in height SD over time; or height below the expected range around the parental target height (height SD − target height SD < −1.5, or < −1.6 relative to the conditional target height, which corrects for assortative mating and the parent-offspring correlation) [1]. SGA refers to birth weight and/or length below −2 SD for gestational age; "short SGA" refers to SGA that remains with short stature [1, 14]. Isolated short stature is that which occurs without other clinical findings, regardless of birth size [1]. Genetic testing covers sequencing, copy number analysis, karyotyping and methylation analysis; a genetic cause is any (likely) pathogenic chromosomal alteration, structural or copy number variant (CNV), sequence variant or methylation defect with causal evidence [1]. Turner syndrome, SHOX deficiency, ACAN/NPR2, Silver-Russell, Temple, GH deficiency, hypopituitarism, RASopathies, dysplasias and primordial dwarfism are covered here because of their role in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Phases of growth and dominant regulators

Early embryonic growth depends mainly on IGF-1 and IGF-2; fetal and early neonatal growth depends mainly on IGF-1; growth in later childhood depends on GH and IGF-1 [13]. This leads to the first clinical question in a short child: whether the restriction began before birth (IGF axis disorders, imprinting, primordial dwarfism, many dysplasias and syndromes) or after it (GH deficiency, GH insensitivity, late-expressing dysplasias, systemic diseases) [4, 13]. Bone elongation occurs at the growth plate, where chondrocyte proliferation and hypertrophy are regulated by endocrine signals (GH, IGF-1, thyroid hormones, sex steroids), paracrine signals (C-type natriuretic peptide, Indian hedgehog, fibroblast growth factors) and the extracellular matrix; the 2026 guideline therefore distinguishes primary growth disorders (intrinsic to the plate) from secondary disorders (extrinsic: nutrition, chronic disease, endocrinopathies) [1].

2.2. The GH–IGF axis

GH binds to its receptor (GHR) and activates the JAK2–STAT5B pathway, which induces hepatic IGF-1, its binding protein 3 (IGFBP-3) and the acid-labile subunit (ALS), forming a circulating ternary complex [8]. Genetic defects produce distinct biochemical patterns, useful for guiding testing:

The 2026 guideline adds QSOX2 and STAT3 to the targeted GH insensitivity panel and points out that RASopathies can mimic GH insensitivity, and that children with slow growth, borderline IGF-1 and a normal GH response to stimulation tests may have normal GH sensitivity [1]. For secretion defects (GH1, GHRHR, GHSR, pituitary development genes), according to the guideline, the genetic diagnosis has three practical consequences: type II GH deficiency due to an AD GH1 variant requires monitoring of corticotrophin (ACTH), thyrotrophin (TSH) and gonadotrophins; PROP1 variants with a pituitary mass avoid surgery, because the mass tends to regress; monoallelic GHSR variants cause "isolated partial GH deficiency" with good catch-up on treatment [1].

2.3. Growth plate and cartilage matrix

SHOX (PAR1 region of Xp22.33 and Yp11.32) encodes a homeobox transcription factor expressed in hypertrophic chondrocytes; haploinsufficiency mainly affects the middle segments of the limbs. About 80–90% of causal alleles are deletions, from a single exon up to 10 kb–2.5 Mb or more, including deletions of the downstream enhancers alone with the gene intact; sequencing alone detects only 10–20% of causal alleles [7, 8]. Being pseudoautosomal, it behaves as autosomal: dominant in Léri-Weill dyschondrosteosis (LWD) and SHOX-related short stature, recessive in Langer mesomelic dysplasia (adult height −5.5 to −8.9 SD), with father-to-son transmission possible; all of Turner syndrome is haploinsufficient for SHOX [8, 68]. In LWD, height in childhood ranges from −4.2 to −0.2 SD and adult height from 135 to 164 cm in women and from 156 to 171 cm in men, with more severe expression in females; short stature and Madelung deformity are expressed independently and each can be the only manifestation [71]. Mean adult height is −2.2 SD, one third have calf hypertrophy and many children under 6 years have no evident signs, so examination of the parents' wrists guides familial cases [72].

ACAN (aggrecan) causes a dominant spectrum of short stature with advanced bone age, with or without early osteoarthritis and osteochondritis dissecans; NPR2 (natriuretic peptide receptor B) causes short stature with non-specific skeletal anomalies in the heterozygous state, acromesomelic dysplasia Maroteaux type in the homozygous state and overgrowth (Miura type) with gain-of-function variants; IHH causes brachydactyly A1 and mildly disproportionate short stature, with shortening of the middle phalanges of the 2nd and 5th fingers in half of cases [8, 14]. Gain-of-function FGFR3 causes achondroplasia, hypochondroplasia (p.(Asn540Lys) variant in about 70%) and, rarely, proportionate short stature [4, 73, 74].

2.4. Fundamental cellular processes: primordial dwarfism

The forms of primordial dwarfism result from defects in universal cellular processes, which explains the severe prenatal restriction with microcephaly and the lack of response to growth-promoting drugs: DNA replication and damage response (ATR, RBBP8, CENPJ, CEP152 in Seckel syndrome; ORC1, ORC4, ORC6, CDT1, CDC6, CDC45, GMNN, MCM5 in Meier-Gorlin syndrome), centrosome and spindle organisation (pericentrin, PCNT, in microcephalic osteodysplastic primordial dwarfism type II, MOPD II), minor intron splicing (RNU4ATAC, U12 spliceosomal RNA, in MOPD I/III) and DNA repair (BLM, Fanconi genes, NBN, LIG4, XRCC4) [9, 14, 75–77]. The ubiquitin-proteasome pathway appears in several syndromes: CUL7, OBSL1 and CCDC8 in 3M syndrome (65%, 30% and 5% of cases), TRIM37 in Mulibrey nanism and UBR1 in Johanson-Blizzard syndrome [78–80].

2.5. Genomic imprinting

Growth restriction due to imprinting disturbance involves 11p15.5 (hypomethylation of imprinting control region 1 (ICR1), H19/IGF2, in 35–67% of Silver-Russell cases), maternal uniparental disomy (UPD) of chromosome 7 (7–10%), 14q32 (Temple syndrome: UPD(14)mat, paternal deletion or loss of methylation), UPD(20)mat or 20q13.2 deletion with loss of paternally expressed GNAS, and maternally transmitted gain-of-function CDKN1C variants in IMAGe syndrome [9, 14, 81]. Multilocus imprinting disturbances may be associated with maternal variants in genes of the subcortical maternal complex (NLRP2, NLRP5, NLRP7, PADI6, KHDC3L), present in 20–30% of mothers with reproductive problems of children with these disturbances [9].

2.6. The RAS/MAPK pathway and other signalling pathways

The RASopathies (Noonan, Costello, cardiofaciocutaneous and related syndromes) activate the RAS/MAPK pathway; short stature is associated with low IGF-1 and IGFBP-3 and, in PTPN11 variants, with mild post-receptor GH resistance [10]. The SHOC2 variant NM_007373.4:c.4A>G p.(Ser2Gly) is associated with Noonan features with GH deficiency [10, 74]. Other pathways: PIK3R1 (PI3K pathway; SHORT syndrome, with insulin resistance), FGD1 (guanine nucleotide exchange factor for Rho GTPases; Aarskog-Scott syndrome, X-linked), ROR2/WNT5A/DVL1/DVL3 (non-canonical WNT pathway; AR and AD Robinow syndrome), SRCAP (chromatin remodelling; Floating-Harbor), FAM111A (Kenny-Caffey syndrome with hypoparathyroidism; recurrent variant NM_001312909.2:c.1706G>A p.(Arg569His)) [4, 74, 82–85].

2.7. Genetic architecture, penetrance and interpretation

Short stature may be monogenic (one variant necessary and sufficient), digenic or oligogenic, or classically polygenic; polygenic scores for familial short stature and adult height reach an accuracy of 0.84–0.94 in research studies [1]. In families with short stature, assortative mating (short people tend to have short partners), incomplete penetrance, variable expressivity and phenocopies confound segregation analysis, and variants in syndromic or dysplasia genes should be interpreted with caution when the characteristic features are absent [1]. The case of the FGFR3 variant NM_000142.5:c.1619A>G p.(Asn540Ser), described in hypochondroplasia and in a three-generation family with proportionate short stature without radiological changes, illustrates that different substitutions at the same codon can have different expression [73, 74]. The genes with the strongest evidence of association with isolated short stature without other findings are ACAN, COL2A1, FBN1, FGFR3, GH1, GHR, GHSR, IGF1R, IHH, NF1, NPR2, PTPN11 and SHOX [1].

2.8. Allelic disorders of diagnostic relevance

3. Clinical Spectrum and Manifestations by System

3.1. Auxological patterns

Four axes describe the growth phenotype: onset (prenatal or postnatal), proportions (proportionate or disproportionate; rhizomelic, mesomelic or acromelic; predominantly short trunk or limbs), relationship with head circumference (microcephaly, relative macrocephaly) and trajectory (parallel to a low centile, deceleration, loss of the pubertal growth spurt) [1, 4, 87]. About 88% of low birthweight newborns catch up in the first year; catch-up may be later in preterm infants and fails more often when intrauterine restriction was early [4]. Among those born SGA, at least 90% catch up spontaneously to above −2 SD, but on average remain 1 SD below target height; 5–10% have persistent short stature, and in low- or middle-income countries only 50–60% catch up [1, 14].

In skeletal dysplasias, clinical groups guide the diagnosis: short limbs with the trunk less affected (achondroplasia, hypochondroplasia, acromesomelic dysplasias, pseudoachondroplasia); short limbs and trunk (diastrophic dysplasia, Kniest); short trunk with the limbs less affected (spondyloepiphyseal and spondylometaphyseal dysplasias); epiphyseal changes (multiple epiphyseal dysplasias, chondrodysplasia punctata); metaphyseal changes (difficult to distinguish from rickets on radiography alone); and changes in bone density (increased in osteopetrosis and pycnodysostosis, decreased in osteogenesis imperfecta and hypophosphatasia) [87]. Many of these changes only become evident after 2–3 years (hypochondroplasia) or progress with age (disproportion in SHOX, ACAN and NPR2 deficiency) [1, 4, 14].

3.2. Natural history by entity

3.3. Extra-auxological manifestations by system

Endocrine and metabolic: hypoglycaemia in Laron syndrome and Silver-Russell (with hyperhidrosis in up to 67%); insulin resistance and diabetes in SHORT syndrome (frequent after 15 years), MOPD II (with early dyslipidaemia and cardiomyopathy) and Mulibrey; hypothyroidism in about 30% of cases of Johanson-Blizzard; hypoparathyroidism with recurrent hypocalcaemia, hypomagnesaemia and hyperphosphataemia in Kenny-Caffey; adrenal insufficiency and hypogonadotrophic hypogonadism in IMAGe; resistance to PTH and other hormones in Albright hereditary osteodystrophy; advanced bone age in carriers of ACAN and GNAS variants [1, 4, 8, 9, 77, 79–82, 85].

Neurodevelopment: normal in most dysplasias, 3M, SHOX deficiency and Mulibrey; intellectual disability frequent in Cornelia de Lange, Rubinstein-Taybi, Seckel, MOPD I, Johanson-Blizzard and IGF-1 deficiency; expressive language delay in Floating-Harbor; mild learning difficulties, especially of speech, in Silver-Russell due to UPD(7)mat [4, 8, 75, 80, 89].

Immunity and haematology: immune dysregulation and interstitial pneumonia in biallelic STAT5B deficiency; immunodeficiency in Nijmegen and LIG4; bone marrow failure in Fanconi anaemia; haematological changes in Seckel syndrome [8, 14, 75].

Cancer predisposition: DNA repair disorders (Bloom, Fanconi, Nijmegen, LIG4, XRCC4) are associated with cancer risk; Mulibrey is associated with benign tumours (ovarian fibrothecoma in 55%) and malignant tumours (15%, including Wilms tumour in 4%); Costello syndrome is associated with rhabdomyosarcoma in childhood [13, 14, 79].

Cardiovascular and vascular: constrictive pericarditis in Mulibrey (50% with heart failure; pericardiectomy beneficial in about two thirds); moyamoya disease and aneurysms with a risk of stroke in MOPD II; congenital heart disease in 50–80% in Noonan syndrome [10, 77, 79].

Skeletal and articular: Madelung deformity in LWD; early osteoarthritis and osteochondritis dissecans with ACAN; odontoid hypoplasia with a risk of spinal cord compression in spondyloepiphyseal dysplasia congenita and mucopolysaccharidosis IV; lumbar canal stenosis in the adolescent with achondroplasia; hip dysplasia and severe coxa vara in MOPD II [8, 75, 87].

Gonadal: male subfertility in 3M and Kenny-Caffey; premature ovarian insufficiency in Mulibrey and MOPD II; precocious puberty in Temple syndrome and MOPD II; rapid advance of bone age at puberty in Silver-Russell [9, 11, 14, 75, 79, 85].

3.4. Treated disease versus natural history

The heights in Table 3.2 describe untreated patients or historical series. On somatropin, adult height improves on average by 1.25 SD in SGA children (systematic review of 4 trials, 391 children), by about 7.2 cm in Turner syndrome (meta-analysis of two randomised trials, with 40–50% of treated girls reaching normal height versus 4–16% of untreated girls) and by 7–10 cm in SHOX deficiency; in Noonan syndrome the gain in height SD ranges from 0.6 to 1.8 [7, 10, 14, 17]. In primordial dwarfism, 3M and severe dysplasias, the response is poor or absent [14, 87, 88].

4. Clinical Recognition and Warning Signs

4.1. When to suspect and when to refer

Detection depends on serial measurements recorded on appropriate charts (national charts or those most suitable for the country) [14]. The 2026 Italian Delphi consensus proposes, for primary care, three criteria for early detection, alone or in combination: height below −2 SD (or below the 3rd centile) for age, sex and population; height inappropriate for the genetic target height; and growth velocity below −1 SD over the previous 6 months [15]. The Dutch criteria, tested on longitudinal data from four patient groups and three population samples, showed that from 0 to 3 years a height below −3 SD or two measurements below −2.5 SD detect about 30% of pathology with less than 1% false positives, and that from 3 to 10 years a distance from target height greater than 2 SD with height below −2.0 SD is the best criterion; combined with the severe short stature rule (< −2.5 SD) and with height deviation, it detects 85.7% of Turner syndromes and 76.5% of children who are short because of various diseases, with 1.5–2% false positives [92].

For children born SGA, the 2023 international consensus recommends monitoring of weight, length, head circumference and weight/length every 3 months in the first year, six-monthly in the second and annually thereafter, and referral to paediatric endocrinology when height remains below −2.5 SD at 2 years or below −2 SD at around 3–4 years without catch-up in the previous 6 months; very preterm birth (< 28 weeks), severe SGA (< −3 SD) or a suspected syndrome justify early referral [14].

The perspective of the Growth Hormone Research Society (GRS, 2019) adds as a criterion a fall in height SD of at least 0.3 SD per year that is not explained by the infant's channelling towards its target trajectory, prepubertal deceleration or pubertal delay, and points out that GH deficiency does not require a height threshold, especially in infants with hypoglycaemia or midline defects [60].

4.2. Warning signs of a genetic cause

The 2026 international guideline identifies findings that increase the probability of a genetic cause and justify testing: a family history compatible with autosomal dominant, recessive, X-linked or mitochondrial inheritance, or a child's height much lower than that of both parents; major malformations or a neurodevelopmental disorder; height below −3 SD; microcephaly; absolute or relative macrocephaly; disproportion (sitting height/height or arm span/height outside ±2.5 SD); syndromic features; clinical or radiological skeletal anomalies; and, in any girl with unexplained short stature, the possibility of Turner syndrome [1]. In practice, the clinical indicators of skeletal dysplasia are disproportion, brachydactyly, pathological fractures, cranial nerve palsies without neuromuscular disease, limb asymmetry, severe or progressive kyphoscoliosis, reduced or increased joint mobility and a waddling gait [1].

4.3. Urgent signs

Some genetic causes of short stature have acute complications that precede the diagnosis: fasting hypoglycaemia in Laron syndrome and Silver-Russell (GH tests with fasting are contraindicated in Silver-Russell); adrenal insufficiency in IMAGe, which usually presents with neonatal hyperpigmentation but can cause crisis and unexpected death; hypocalcaemic tetany and seizures in Kenny-Caffey; spinal cord compression in dysplasias with odontoid hypoplasia; apnoea and difficult intubation in Hallermann-Streiff and Silver-Russell; and stroke due to moyamoya vasculopathy in MOPD II [8, 9, 77, 81, 85, 87, 91].

4.4. Prenatal and neonatal detection

Growth restriction is rarely detectable on ultrasound before 28 weeks [13]. Short limbs, with or without a narrow thorax, on the 20-week scan are non-specific findings that do not allow a specific diagnosis without additional information; in mild forms the ultrasound is often normal [87]. Achondroplasia is suspected or diagnosed before birth in 80–90% of cases, at a median gestational age of 29–32 weeks; agenesis of the septum pellucidum may suggest septo-optic dysplasia (about 1/10,000 live births) [15]. In 3M, short limbs detected in utero are usually interpreted as growth restriction, unless there is an affected sibling [88]. The sources consulted do not describe newborn screening programmes aimed at the genetic causes of short stature.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles

There are no diagnostic criteria for "short stature of genetic cause" as a single entity; diagnosis is a stepwise process whose first step is confirmation of short stature with rigorous auxology; it then excludes treatable secondary disorders, assigns the child to a descriptive category and chooses the genetic test appropriate to that category [1]. Complete clinical assessment (history, examination, screening tests and radiographs) diagnoses most secondary disorders, such as coeliac disease and hypothyroidism, and Turner syndrome in girls; when it does not lead to a diagnosis, the child is classified as having isolated or non-isolated short stature (suspected skeletal dysplasia, suspected GH/IGF-1 axis defect, or syndromic), and only at the end of the work-up receives an aetiological classification [1].

5.2. Auxology

Measurement: below 2 years, supine length on an infantometer, with two people (head in the Frankfurt plane, knees extended, feet at 90°); thereafter, standing height without shoes on a stadiometer (Harpenden or wall-mounted tape with a sliding headboard), with the Frankfurt plane horizontal and gentle upward traction under the mastoids to reduce diurnal variation; recorded to the last completed 0.1 cm; in preterm infants, corrected age [15, 93]. Growth velocity is calculated from measurements 6–12 months apart [15]. The height standard deviation score (SDS) refers to the most recent and appropriate population chart; norms derived mainly from white populations may not be accurate in other groups, which requires comparing the child with parents and siblings [1, 93].

Parental target height: for girls, [(father's height − 13) + mother's height]/2, with a target range of ±9 cm; for boys, [(mother's height + 13) + father's height]/2, with a range of ±10 cm (13 cm is the mean difference between adult men and women in the United Kingdom) [4]. Target height is misleading when one of the parents has a genetic cause of short stature, which is frequent in autosomal dominant forms [1, 4]. The 2026 guideline recommends expressing the difference in SD (height SD − target height SD) and, ideally, using the conditional target height [1].

Proportions: measure head circumference, arm span (distance between the tips of the middle fingers with the arms in horizontal abduction), sitting height and upper and lower segments [1, 87]. Height equal to arm span suggests normal proportions; height less than arm span suggests a short trunk; height greater than arm span suggests short limbs; when limbs and trunk are both short, height may equal arm span and mask the disproportion [87]. The upper/lower segment ratio decreases with age (in white children, about 1.15–1.18 at 4 years, close to 1.0 at 8–9 years and 0.93–0.96 between 12 and 16 years, as read from the McKusick chart) and is 0.05–0.1 lower in black children at all ages [93]. The 2026 guideline uses as the threshold for disproportion sitting height/height or arm span/height outside ±2.5 SD; in SHOX deficiency, sitting height/height above +2 SD, or above +1 SD with arm span ≥ 3 cm less than height, increase the probability of the diagnosis, but normal proportions do not exclude it [1]. The Rappold score (2007), derived from 1608 short children, 68 with SHOX deficiency, includes arm span/height < 96.5%, sitting height/height > 55.5%, body mass index above the 50th centile, cubitus valgus, short or bowed forearm, appearance of muscular hypertrophy and dislocation of the ulna [7].

The Delphi consensus on ISS adds operational auxological criteria: measure supine length below 2 years and standing height thereafter; use validated population charts from 2 years and those of the World Health Organization (WHO) below that age when national norms do not exist; calculate velocity from at least two measurements at least 6 months apart; measure biological parents and siblings; investigate the child with height below −2 SD or more than 2 SD below target height; and interpret velocity, predicted adult height and deviation from target height together, none of which confirms or excludes ISS on its own [70]. Prediction of adult height from bone age (Bayley-Pinneau, Roche-Wainer-Thissen or Khamis-Roche methods) only applies from 6 years in girls and 7 in boys, is imprecise when maturation is delayed or the growth pattern is abnormal, and varies with the bone age reading method (Greulich-Pyle or Tanner-Whitehouse); it should not be the sole criterion for diagnosis or treatment [70]. On examination, the consensus uses as the threshold for disproportion a sitting height/height ratio or an arm span−height difference beyond ±2 SD for sex and age, stricter than the ±2.5 SD of the genetic testing guideline; a BMI below the 3rd centile or above the 85th centile suggests a systemic, endocrine or nutritional cause, and precocious puberty in a short child requires endocrine assessment [1, 70]. A bone age delayed by 2 or more years supports CDGP without confirming it; the child keeps the provisional label of unexplained short stature and is reassessed at pubertal milestones, with delayed puberty defined as the absence of breast development at 13 years in girls and of testicular enlargement at 14 years in boys [70].

5.3. History and physical examination

The history includes a three-generation pedigree with heights (measured whenever possible), consanguinity, the parents' age at puberty, family history of early osteoarthritis or hip replacement (epiphyseal involvement), pregnancy (maternal disease, drugs, alcohol, ultrasound scans showing short limbs or restriction, amniotic fluid volume — oligohydramnios in placental insufficiency, polyhydramnios in cardiofaciocutaneous, Costello and Bartter syndromes), birth weight, length and head circumference corrected for gestational age, growth curve, feeding, chronic diseases, orthopaedic surgery, fractures and development [1, 4, 13, 87]. The examination looks for dysmorphic features, skin changes (café-au-lait macules in Silver-Russell and Fanconi, telangiectasias in Bloom, acanthosis nigricans in lipodystrophies and Donohue syndrome), hands and feet (brachydactyly, broad thumbs, short metacarpals, clinodactyly), deformities and asymmetries, pubertal stage, and signs of hypothyroidism, GH deficiency and renal or cardiac disease [1, 4, 13]. The guideline recommends deep phenotyping before requesting the test, ideally with Human Phenotype Ontology (HPO) terms that feed the bioinformatic analysis [1].

5.4. Screening tests

Every child with short stature should have a laboratory assessment, as screening or guided by the clinical picture, to detect treatable disorders [1]. The Italian consensus lists as mandatory in primary care: full blood count, fasting blood glucose, creatinine, sodium and potassium, transaminases and gamma-glutamyltransferase, C-reactive protein, calcium, phosphate and alkaline phosphatase, coeliac disease screening, venous blood gas below 2 years, IGF-1, TSH and free T4, FSH in girls under 2 or over 9 years, and urinalysis [15]. The GRS (2019) preferred clinically guided tests, citing the low yield of routine screening in children with a velocity above 5 cm/year in a tertiary centre, with the possible exception of coeliac disease; the 2026 guideline accepts both strategies (screening or targeted assessment) [1, 60]. For coeliac disease, the 2020 guideline of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends total IgA and IgA anti-transglutaminase 2 antibodies; antibodies against deamidated gliadin peptides should not be used as the initial test and IgG tests are reserved for IgA deficiency [16]. In SGA children, the 2023 consensus indicates thyroid function and IGF-1, with IGFBP-3 if IGF-1 is low, and a GH stimulation test only when deficiency is suspected [14]. Targeted tests: faecal elastase 1 when exocrine pancreatic insufficiency is suspected (Shwachman-Diamond, Johanson-Blizzard; low values in meconium, normal by day 3 in term infants and by 2 weeks in those born before 28 weeks), aldosterone with a history of polyhydramnios (Bartter), insulin when Donohue syndrome is suspected, immunoglobulins and lymphocyte subsets when immunodeficiency is suspected, urinary glycosaminoglycans, very long chain fatty acids and sterol profile when a metabolic bone or storage disease is suspected [13, 87].

The Delphi consensus on ISS recommends, when the clinical assessment is normal, a minimum screen before labelling the child as ISS: TSH and free T4; IgA anti-tissue transglutaminase with total IgA (in IgA deficiency, IgG-based tests, such as IgG anti-transglutaminase or IgG antibodies against deamidated gliadin peptides, in agreement with ESPGHAN); IGF-1, or IGFBP-3 below 3 years; and markers of systemic disease according to clinical suspicion (full blood count, erythrocyte sedimentation rate, C-reactive protein, renal and liver function, antithyroid antibodies) [70]. Part of the panel noted the low yield of these tests in asymptomatic children with normal velocity [70]. The same consensus recommends testing for Turner syndrome in all girls with unexplained short stature, whether or not there are clinical signs, by peripheral blood karyotype, with high-resolution karyotype or fluorescence in situ hybridisation (FISH) if the karyotype is normal and suspicion persists; some centres have replaced the karyotype with microarray or genome sequencing [70]. The supplementary material of the 2026 guideline proposes a list of possible screening components with their respective context: full blood count (Fanconi anaemia, Kabuki syndrome, haemoglobinopathies, coeliac disease, inflammatory bowel disease), inflammatory markers and faecal calprotectin (inflammatory bowel disease, especially after 10 years with a falling BMI SD, as it is rare before that age), sodium, potassium, creatinine or cystatin C, calcium, phosphate, alkaline phosphatase and parathyroid hormone, blood gas (renal tubular acidosis, especially below 3 years), liver function tests and blood glucose (glycogen storage diseases), anti-transglutaminase antibodies with total IgA, IGF-1 (low in GH deficiency or insensitivity and in malnutrition; high in IGF1R haploinsufficiency), IGFBP-3 (most useful below 3 years), free T4 and TSH, urine dipstick (proteinuria, glycosuria) and genetic tests (karyotype, microarray, exome or genome, methylation) [1].

5.5. Bone age and skeletal survey

A radiograph of the left hand and wrist for bone age is recommended in all children with short stature and should be requested before referral [1, 15]. A delayed bone age is typical of secondary disorders (hypothyroidism, GH deficiency) and maturational delay; most primary disorders have a normal or delayed bone age, but ACAN and GNAS heterozygotes frequently have advanced bone age; its usefulness is limited below 3 years [1]. In familial short stature, bone maturation is concordant with chronological age; in constitutional delay it is concordant with height age [4]. In SGA children treated with GH, annual bone age is not recommended in prepubertal children, but it is worth assessing at around 8 years and from puberty onwards, because an advance may signal ACAN [14]. The same radiograph may show anatomical signs (Madelung deformity in SHOX deficiency; shortening of the middle phalanges with cone-shaped epiphyses in the IHH variant) [1, 14].

A skeletal survey is indicated when skeletal disease is suspected, especially with disproportion, bone deformities or mineralisation changes: skull and spine in anteroposterior and lateral views, anteroposterior pelvis, all four limbs (unilateral if there is no asymmetry) and hands and feet; in the newborn, anteroposterior and lateral "babygram"; the radiation dose is relatively low [1]. Reading should be by an experienced paediatric radiologist or a clinician trained in pattern recognition; some changes are subtle in infancy (hypochondroplasia) or evolve over time, and a normal survey with delayed bone age points towards endocrine assessment [1, 87]. Cervical spine radiographs in flexion and extension (before anaesthesia) and magnetic resonance imaging (MRI) of the neuraxis are indicated in dysplasias with odontoid hypoplasia or other vertebral complications [87].

5.6. Endocrine assessment

IGF-1 is part of the screen; a low IGF-1 requires exclusion of secondary causes (malnutrition, hypothyroidism, chronic corticosteroid therapy) before concluding that there is GH deficiency or insensitivity [8, 15]. GH stimulation tests, thresholds and hypothalamic-pituitary MRI have their own criteria in GH deficiency; MRI without contrast (T2-DRIVE sequences) of the hypothalamic-pituitary region and brain is recommended in severe short stature with GH deficiency or with multiple pituitary deficiencies [15]. In Silver-Russell, tests involving fasting are contraindicated because of the risk of hypoglycaemia [9]. The stimulation test is unnecessary when there is an evident alternative diagnosis (Turner, Noonan, Prader-Willi, aggrecan deficiency, SHOX deficiency, chronic renal failure, Silver-Russell, SGA with persistent short stature), unless GH deficiency is additionally suspected; current GH assays with monoclonal antibodies give values about 40% lower than older ones, and most GRS participants suggested a threshold of 7 ng/mL, assay-dependent and to be set by each national society [60]. Severe primary IGF-1 deficiency is defined, in the US mecasermin label, by height ≤ −3.0 SD, basal IGF-1 ≤ −3.0 SD and normal or raised GH; in the European label, by height ≤ −3.0 SD, basal IGF-1 below the 2.5th centile for age and sex, GH sufficiency and exclusion of secondary forms, with a recommendation to confirm by an IGF-1 generation test [21, 22]. An IGF-1 above the mean, or raised on GH, in an SGA child with a small head circumference points to IGF-1 resistance (IGF1R) [1, 14].

For the Delphi consensus, an IGF-1 below −2 SD strongly suggests GH deficiency, but a normal value does not exclude mild forms; an IGFBP-3 below −2 SD is also abnormal, with greater specificity in early childhood, and the combination of low IGF-1 and IGFBP-3 increases specificity for GH deficiency or resistance [70]. The differential diagnosis of low IGF-1 and IGFBP-3 includes, in addition to GH deficiency or resistance, ALS deficiency, malnutrition, anorexia nervosa, type 1 diabetes, chronic inflammatory diseases (Crohn's disease, juvenile idiopathic arthritis) and coeliac disease [70]. ISS usually presupposes a stimulated GH peak of 7.5–10 µg/L or more in two tests, with normal IGF-1 and IGFBP-3, but thresholds vary with the assay and the region, and the need for the test in healthy children with adequate velocity is disputed [70]. The North American PES guideline (2016) recommends, with high-quality evidence, not using the result of stimulation tests as the sole diagnostic criterion for GH deficiency, because of their limited sensitivity and specificity, and requiring laboratories to use GH assays harmonised with the somatropin standard IRP IS 98/574 (22 kDa recombinant isoform), because different assays classify the same sample differently [94, 95]. It waives the stimulation test when auxological criteria, a hypothalamic-pituitary defect (major congenital malformation, such as ectopic posterior pituitary with pituitary hypoplasia and abnormal stalk, tumour or irradiation) and deficiency of at least one other pituitary hormone coexist, and in the newborn with hypoglycaemia whose GH does not exceed 5 µg/L and who has another pituitary deficiency and/or this imaging triad; a low GH during spontaneous hypoglycaemia is not, on its own, sufficient for the diagnosis (conditional recommendations) [94]. Outside these scenarios, the diagnosis requires an insufficient response in two tests with different stimuli, which may be performed in sequence on the same day [94]. The 10 µg/L threshold, adopted to identify partial forms, is not based on controlled studies to adult height and lies only slightly below the mean of children with normal growth, whose 5th centile is below 5 µg/L in most tests; in 236 prepubertal children from the North American National Cooperative Growth Study (NCGS) registry, the gain in height SD in the first year was indistinguishable between peaks of 5–10 µg/L and above 10 µg/L, gains greater than 1.5 SD occurred only with peaks below 5 µg/L, and the specificity of the 10 µg/L threshold was estimated at 25% [94]. Reproducibility is limited (in a French registry of 3233 cases, the correlation between the peaks of two tests in the same patient was 0.35–0.6) and obesity reduces the peak without BMI-corrected paediatric thresholds being available, so hypothyroidism and hypercortisolism are excluded before testing the obese child [94]. The guideline suggests sex steroid priming before the test in prepubertal boys over 11 years and prepubertal girls over 10 years whose predicted adult height is within −2 SD of the mean, to avoid treating constitutional delay of growth and puberty; it proposes 17β-oestradiol (not ethinylestradiol) 2 mg orally (1 mg if weight is below 20 kg) on each of the two nights before the test or, in boys, depot testosterone 50–100 mg intramuscularly one week before; the evidence is better in boys and extrapolated to girls, and the recommendation applies only to children never treated with GH [94]. With 1–2 mg of oestradiol, the lower limit of the 95% confidence interval (95% CI) of the GH peak in 44 children with ISS rose from 3.7 to 8.3 µg/L, without changing the response in 15 children with GH deficiency proven by other criteria [94]. The guideline advises against studying spontaneous GH secretion for clinical diagnosis [94].

5.7. Indications for genetic testing (2026 international guideline)

The guideline uses the GRADE methodology: "recommends" corresponds to a strong recommendation and "suggests" to a weak one; the quality of evidence ranges from very low (⊕○○○) to high (⊕⊕⊕⊕); statements based on expert consensus are "good clinical practice", without a grade [1].

The 2026 Italian consensus, aimed at paediatricians, approved the statement that genetic testing is indicated when history, examination, tests and radiographs point to a genetic cause, but did not reach consensus on karyotype prescription by any paediatrician (37.4% disagreement) or on the obligation for all paediatricians to master genetic tests (24.5%), partly because of regional prescription and reimbursement rules [15]. The 2023 SGA consensus recommends assessment by a geneticist in the presence of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability or signs of dysplasia, and genetic testing in SGA children with persistent short stature without another cause [14].

5.8. Techniques, capabilities and limitations

In girls, the GRS (2019) accepts the SNP array as an alternative to karyotyping when there is no clinical suspicion of Turner, as it also detects CNVs and most uniparental disomies with equivalent sensitivity for Turner; with a 46,XX karyotype and strong suspicion, it recommends microarray or FISH on another tissue (buccal mucosa, urine) [60]. The 2024 Turner guideline keeps the karyotype of ≥ 30 metaphases as first line and notes the limited sensitivity of microarray for low-level mosaicism [17].

Limitations that a negative report does not resolve: sequencing of SHOX alone detects only 10–20% of causal alleles, because most are deletions; in Johanson-Blizzard syndrome, exonic deletions and duplications of UBR1 are frequent and require MLPA when sequencing does not find both alleles; microarray has limited sensitivity for low-level 45,X mosaicism; the exome does not analyse methylation or most non-coding regions; and in Silver-Russell 30–40% of patients who meet the clinical criteria remain without molecular confirmation [1, 8, 9, 17, 80]. A negative test does not exclude a genetic cause, and a proportion of detectable variants is not equivalent to the clinical sensitivity of the test.

5.9. Algorithm by clinical category

The algorithm of the 2026 guideline starts from complete clinical assessment and exclusion of non-genetic secondary disorders and divides children into four categories [1]:

In girls, Turner testing precedes or accompanies any other step [1, 17]. In SGA children with persistent short stature who are candidates for GH, especially with microcephaly, dysmorphic features or delay, the guideline recommends genetic testing before starting treatment and, when appropriate, chromosome breakage testing with sister chromatid exchange studies for Bloom, ataxia-telangiectasia, Fanconi and Nijmegen [1]. In current European practice, exome with a virtual panel or full analysis is the most used strategy; the guideline anticipates that the genome (short-read or long-read) will replace physical panels [1].

5.10. Diagnostic yield

The systematic review underpinning the guideline included 134 studies (from 1163 records): yield of 4.4% (95% CI 3.3–5.7) for candidate gene testing, 16.3% (8.1–26.4) for microarray, 21.6% (15.1–28.9) for panels and 33.3% (26.4–40.6) for exome [1, 96]. With exome, the yield was 15.1% (10.4–20.6) in short stature labelled idiopathic, 50.8% (43.2–58.4) in syndromic short stature and 69.8% (61.1–77.9) in suspected skeletal dysplasia; excluding variants of uncertain significance (VUS), all yields decrease [1, 96]. The predictors most associated with higher yield were facial dysmorphism and skeletal anomalies; the most recurrent genes were PTPN11, NF1, COL2A1, ACAN and FGFR3 [96]. In a cohort of 304 patients studied by exome, the yield was 34% with syndromic features and 11% in isolated short stature [1]. The presence of microcephaly increased the yield from 44% to 56% and from 25% to 83% in two studies of syndromic short stature; a sitting height/height ratio above +2 SD raised the SHOX yield from 3.1% to 13.8% and from 5.7% to 40%, and the NPR2 yield from 17.6% to 28.3%; having at least one parent below −2 SD increased the yield in five studies [1]. SGA status alone does not increase the yield in isolated short stature [1]. The genome added about 8% of diagnoses after a negative exome in a large rare disease cohort [1].

For individual genes, estimates depend on inclusion criteria and methods: SHOX deficiency accounts for 70–90% of LWD and 6–22% of short children without a cause and without signs of LWD with MLPA and Sanger including the enhancers (2–10% with less sensitive methods; 2.4–7% in the series cited by the Oxford Desk Reference, which predate this technique) [4, 7]; NPR2 about 2%, IHH 1.6% and ACAN 1–2% of short SGA and ISS; ACAN 14% of short SGA with bone age advanced by ≥ 6 months and 14.3% in a Chinese cohort with advanced bone age (35.7% with advanced bone age and a family history) [8, 14]; IGF1R 1–2% of short SGA [14]. Karyotyping in short girls without other signs had a yield of 2.5% in two small studies [1].

In short SGA, the supplementary material of the guideline summarises heterogeneous yields: microarray 16–46% (variation attributed to the proportion of syndromic cases); methylation changes at imprinted loci in 6 of 98 short SGA (6%); (likely) pathogenic variants in 8 of 55 isolated short SGA (15%) by exome or panel; 34% by exome in syndromic SGA; CNVs in 11 of 24 SGA with persistent short stature, dysmorphic features and/or delay (46%); and 11–55% with the combination of panel, exome and methylation used since 2020 [1]. When Silver-Russell is suspected, the Netchine-Harbison score guides the request, and the work-up begins with methylation of 11p15, chromosome 7 and 14q32, moving on to sequence variants, CNVs and uniparental disomies if negative [1].

5.11. Interpretation, report and reanalysis

The report should state the gene, the reference transcript with version, the Human Genome Variation Society (HGVS) nomenclature (c. and p.), zygosity, inheritance and the ACMG/AMP or ACGS class, contextualised in the phenotype [1]. Many variants found in short children are difficult to classify; segregation helps but is confounded by assortative mating, incomplete penetrance and phenocopies; functional RNA or splicing studies, when the gene is expressed in an accessible tissue, and methylation episignatures may support classification [1]. For monoallelic variants in pituitary development genes with variable penetrance, interpretation should be cautious, especially for novel variants [1]. Reanalysis of exome or genome data should be periodic in persistently unexplained short stature and immediate when new signs appear; samples sequenced before about 2018 may justify resequencing [1].

5.12. Benefits and risks of testing

Benefits: definitive diagnosis; counselling and recurrence risk; an end to unnecessary investigations; diagnosis before full phenotypic expression (in genetic GH deficiency or hypopituitarism, GH can be started at 3–6 months without a stimulation test); treatment decisions; detection of diagnoses in which GH is contraindicated or requires caution; targeted screening for comorbidities; testing of relatives; secondary findings with preventive potential [1]. Risks: false-positive diagnosis, uncertainty of VUS, secondary findings that cause anxiety or unnecessary surveillance, and effects on insurance depending on each country's legislation [1].

5.13. Prenatal and preimplantation diagnosis

With the causal variant identified in the family, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis are possible; serial ultrasound scans follow fetal growth [4, 87]. In FGFR3 dysplasias, non-invasive prenatal testing may be available [87]. In Turner syndrome, the prenatal diagnosis should be confirmed by a postnatal blood karyotype [17]. In Silver-Russell, reliable prenatal testing for loss of paternal methylation of 11p15 ICR1 is not possible, and a prenatal or preimplantation result does not reliably predict clinical severity [9].

6. Differential Diagnosis

6.1. Comparative table

6.2. Normal variants and secondary disorders

Familial short stature and constitutional delay account for most referred children; the former has bone age concordant with chronological age and final height estimable from target height, the latter has bone age concordant with height age and a good prognosis for adult height [4]. In the 2026 guideline, children with mild, isolated short stature, parents at the lower limit and non-syndromic, no apparent dominant inheritance and height close to target height are considered to be of probable polygenic origin, without an indication for genetic testing; constitutional delay is a diagnosis of exclusion, and in girls requires exclusion of Turner syndrome [1]. Among the secondary disorders, coeliac disease and hypothyroidism are detectable by laboratory screening; others include renal and cardiac disease, malnutrition, psychosocial deprivation and fetal alcohol exposure [1, 4].

6.3. GH/IGF-1 insensitivity and resistance

This group (ORPHA:181393) includes Laron syndrome and related disorders. Laron syndrome (GHR, AR) presents with severe, proportionate postnatal short stature (≤ −3 SD), low IGF-1 and IGFBP-3 with normal or raised GH, and hypoglycaemia; the European prevalence validated by Orphanet is 1–9 per million (mean 0.3/100,000, source European Medicines Agency — EMA — 2003), and the figure of 4.86/100,000 recorded for China comes from a hospital survey in Shanghai, not from a population study [8]. GH is functionally normal, exogenous GH neither induces IGF-1 nor restores growth, and GH-binding protein, derived from the extracellular domain of the receptor, is often low [35]. The largest founder cohort lives in the provinces of Loja and El Oro, in southern Ecuador, in a population of Spanish origin descended from conversos; unlike the Israeli cohort, these patients had normal or above-normal intelligence, and 22-year follow-up (Guevara-Aguirre 2011, cited by OMIM) recorded a single non-lethal neoplasm and no cases of diabetes, against 17% cancer and 5% diabetes in controls [35]. Heterozygous GHR variants with partial insensitivity (AD) have been found in children labelled ISS: Goddard (1995) identified variants in 4 of 14 children with ISS (3 heterozygous and 1 compound heterozygous, the latter with a poorer response to GH), and Ayling (1997) described dominant mother-to-daughter transmission, suggesting a search for these variants in familial short stature with normal GHBP [8, 36]. Biallelic STAT5B deficiency adds to GH insensitivity an immune dysregulation with potentially fatal interstitial lung disease; the dominant-negative form is milder [8]. In ALS deficiency (IGFALS), the biochemical change (nearly undetectable IGFBP-3) is disproportionate to the short stature, which is only mild to moderate [8]. IGF-1 deficiency (IGF1) is associated with deafness and intellectual disability [8, 63]. PAPPA2 deficiency has raised total IGF-1 and low free IGF-1 [67]. In IGF-1 resistance (IGF1R), IGF-1 is above the mean; in the largest comparative cohort (23 carriers versus 34 treated SGA children), the height gain in the first year of GH was 0.29 versus 0.65 SD, 53% versus 17% were poor responders and insulin resistance was greater during treatment [8].

The 2016 PES guideline suggests diagnosing primary IGF-1 deficiency (GH insensitivity) in four steps, as there is no single test that predicts the response to GH: screening by auxology and low IGF-1 for age and sex; exclusion of secondary causes, namely GH deficiency (stimulation tests), malnutrition (weight-for-length or BMI charts, 3-day dietary record) and liver disease, repeating IGF-1 after nutritional intervention when mild caloric or protein restriction is suspected; measurement of GHBP, in which a very low or undetectable value suggests Laron syndrome and a normal value is not informative, because GHR variants in the exons of the transmembrane or cytoplasmic domains and post-receptor defects present with normal or high GHBP; and, finally, an IGF-1 generation test and genetic testing, both with limitations [94]. These limitations have been quantified: of the 14 NCGS children with ISS and GHBP below −2 SD, only 4 had GHR variants, and GHBP did not predict the response to GH in children without overt Laron syndrome; the IGF-1 generation test (GH for less than 10 days) has no standardised protocol or thresholds, thresholds derived from radioimmunoassay may not apply to current assays, repetition in the same laboratory gave discordant results, and, in one study, 6 of 23 children with GH deficiency did not raise their IGF-1, whereas 5 of 22 with Laron syndrome exceeded the threshold [94]. With very low GHBP, identification of GHR variants confirms Laron syndrome; testing of individual genes is limited to known causes and exome sequencing allows new causes to be identified [94]. Without treatment, height in Laron syndrome lies between −4 and −10 SD in childhood and persists into adulthood (106–142 cm in men, 95–136 cm in women); prenatal growth restriction is possible in IGF1 defects, ALS deficiency and some patients with Laron syndrome, and a prominent forehead, saddle nose, small chin, microcephaly and high-pitched voice strengthen the suspicion [94]. In Kowarski syndrome, a GH1 variant produces bioinactive GH, with low IGF-1, normal or slightly increased GH secretion and a response to exogenous GH; in ALS deficiency the response is poor to both GH and IGF-1, although the growth failure is mild [94].

The supplementary material of the 2026 guideline summarises the profile of genetic defects of the GH–IGF axis with GH insensitivity; it includes QSOX2 (AR, with immunodeficiency and eczema) and STAT3 gain of function (AD), in which growth failure accompanies the immune disease, and points out that STAT3 and IGF2 defects cause short stature independent of GH action and IGF-1 production [1]. The sign "+" indicates presence and "−" absence; combined signs indicate variability between patients; ↓ low, ↑ high, n normal, nd not described.

Source: Table S5 of the 2026 guideline [1].

6.4. Prenatal restriction: differential diagnosis of Silver-Russell

In an SGA child who does not catch up, the differential of Silver-Russell includes monogenic disorders (Bloom, Fanconi, 3M, Meier-Gorlin, IMAGe, osteogenesis imperfecta due to COL1A1/COL1A2, Warsaw syndrome due to DDX11, IGF-1 resistance, Nijmegen, MOPD II, Floating-Harbor), chromosomal anomalies (diploid/triploid mixoploidy, UPD(6)mat, Temple, UPD(20)mat or 20q13.2 deletion) and fetal alcohol syndrome; disproportionate short stature excludes Silver-Russell and suggests dysplasia, and significant microcephaly suggests another aetiology [9]. In 3M, the heel changes and the absence of asymmetry distinguish it from Silver-Russell; several families with "autosomal recessive Silver-Russell" had variants in 3M genes [78, 88]. The SNP array helps to identify regions of homozygosity and to suspect uniparental disomies [9]. Paternal IGF2 variants cause Silver-Russell type 3 (MIM 616489), with severe prenatal and postnatal restriction, relative macrocephaly, triangular face and, sometimes, limb defects and genitourinary anomalies [14, 42]. SOFT syndrome (POC1A, MIM 614813) combines very short long bones with restriction detectable from the second trimester, a final height equivalent to that of a child of 6–8 years, normal psychomotor development, triangular face, high-pitched voice, hypoplasia of the distal phalanges and nails, and sparse hair after puberty [49]. SSMED syndrome (XRCC4, MIM 616541) has short stature and microcephaly from birth with progressive failure, hypergonadotrophic hypogonadism, multinodular goitre and diabetes in adulthood, progressive ataxia in some patients and possible tumour predisposition, without clinically evident immunodeficiency [50]. Other causes of prenatal and postnatal failure: Dubowitz syndrome (AR, eczema, blepharophimosis; a heterogeneous complex that includes dyskeratosis congenita and LIG4), Bartter syndrome (SLC12A1, KCNJ1, SLC12A3; polyhydramnios, prematurity), Donohue syndrome (INSR; markedly raised insulin) and Shwachman-Diamond syndrome (SBDS; pancreatic insufficiency, haematological dysfunction, metaphyseal dysplasia) [13].

6.5. Other syndromes with short stature

Aarskog-Scott syndrome (MIM 305400): mild to moderate short stature (adult height 160–170 cm), delayed bone age, round face with hypertelorism and ptosis, brachydactyly with hyperextension of the distal interphalangeal joints and flexion of the proximal ones, shawl scrotum in 90% and cryptorchidism; the facial phenotype becomes less marked with age; X-linked recessive inheritance (FGD1, Xp11.21), with female carriers sometimes showing facial and hand signs; normal fertility and normal intelligence quotient in most [4, 54, 83]. It is confused with Noonan, Robinow, pseudohypoparathyroidism, Silver-Russell and SHORT [83].

Robinow syndrome (MIM 268310 and 180700): mild to moderate postnatal short stature (93%), hypertelorism and small upturned nose (100%), triangular mouth, short forearms (100%), hemivertebrae (70%), rib anomalies (40%) and genital hypoplasia (94%); the AR form (ROR2) has mesomelic and acromelic short stature, multiple vertebral and rib anomalies and radioulnar dislocation; the AD form (WNT5A, DVL1 — the latter with osteosclerosis —, DVL3) is milder; cognition is normal in most [55, 56, 84].

Mulibrey nanism (MIM 253250; ORPHA:2576): more than 140 cases, 100 in Finland; prenatal restriction with relative macrocephaly, triangular face, yellow dots in the ocular fundus, J-shaped sella turcica, fibrous dysplasia of the long bones, constrictive pericarditis, hepatomegaly, insulin resistance and metabolic syndrome in adolescence, premature ovarian insufficiency and benign and malignant tumours; TRIM37, AR [5, 57, 79].

Johanson-Blizzard syndrome (MIM 243800): restriction of prenatal onset (60%), hypoplasia or aplasia of the alae nasi (100%), midline scalp defect (87%), sensorineural deafness (75%), absence of permanent teeth (90%), exocrine pancreatic insufficiency (100%), hypothyroidism (30%) and diabetes in adolescence; growth may improve with levothyroxine, pancreatic enzymes and fat-soluble vitamins; UBR1, AR [58, 80].

Kenny-Caffey syndrome (MIM 127000): proportionate dwarfism, medullary stenosis of the tubular bones with thick cortex, hypoparathyroidism with episodic hypocalcaemia, microphthalmia and hypermetropia; FAM111A, AD (mostly sporadic); it is treated with calcitriol and calcium, with a risk of nephrocalcinosis. The reference textbook considers that the OMIM nomenclature numbering Sanjad-Sakati syndrome (recessive, with microcephaly and intellectual disability, TBCE) as Kenny-Caffey type 1 perpetuates an error, because it is a different entity [59, 85].

IMAGe syndrome (MIM 614732): severe prenatal and postnatal restriction, congenital adrenal hypoplasia, hypogonadotrophic hypogonadism in boys, hypercalcaemia and hypercalciuria, metaphyseal dysplasia that appears only in early childhood; gain-of-function CDKN1C variants in the PCNA-binding domain, expressed only when maternally transmitted; differential with MIRAGE syndrome (SAMD9, MIM 617053: myelodysplasia, infections, growth restriction, adrenal hypoplasia, genital changes and enteropathy), frequently fatal in the first decade from invasive infection — 6 of 11 patients in the original series died before 2 years [81, 97].

Hallermann-Streiff syndrome (MIM 234100): about 150 cases; proportionate postnatal short stature in two thirds (mean final height 152 cm in women and 155–157 cm in men), bilateral microphthalmia (80%), cataracts (94%), thin beaked nose, hypotrichosis and micrognathia with a narrow upper airway; all cases described in the reference textbook are sporadic [91].

Au-Kline syndrome (MIM 616580): HNRNPK, de novo; normal birth size and frequent but not constant postnatal growth deficiency, craniosynostosis, long palpebral fissures, ptosis, genitourinary anomalies and moderate to severe intellectual disability; many cases were first diagnosed as Kabuki [98].

6.6. Metabolic causes

Inborn errors of metabolism can cause short stature through systemic disease or endocrine involvement: GH deficiency in mitochondrial respiratory chain defects; hypothyroidism in mitochondrial disorders, cystinosis and Allan-Herndon-Dudley syndrome; hypoparathyroidism in LCHAD and trifunctional protein deficiency [99]. The mucopolysaccharidoses and other storage diseases are suspected from coarse facies and hepatosplenomegaly and confirmed by urinary glycosaminoglycans [87].

7. Treatments and Risk Management Strategies

7.1. Principles

Treatment begins with the cause: correction of secondary disorders (gluten-free diet in coeliac disease, levothyroxine in hypothyroidism, nutrition), hormone replacement in pituitary deficiencies and treatment of the specific complications of each syndrome [1, 4]. Children with non-syndromic forms need monitoring of growth velocity by a paediatrician or paediatric endocrinologist; skeletal dysplasias require a plan for preventing complications, discussion of prognosis and surgical options, ideally in a multidisciplinary team (orthopaedics, rheumatology, otorhinolaryngology, endocrinology, physiotherapy, occupational therapy and psychology), with emphasis on as normal a life as possible [4, 87]. Somatropin has no demonstrated benefit in most syndromes and dysplasias: it may accelerate growth in the short term without a gain in adult height, and it is contraindicated or not recommended in disorders with cancer predisposition [4, 14, 87].

7.2. Somatropin: mechanism, indications and doses

Somatropin (recombinant human growth hormone) is given subcutaneously, in weekly doses divided into 6–7 daily injections, with rotation of injection sites to avoid lipoatrophy [18, 20]. Paediatric indications differ between jurisdictions:

The reference doses are those of the guidelines, with the labels as a comparison:

The GRS recommends starting indications unrelated to GH deficiency within the approved ranges, at the upper limit in older SGA children and in late-diagnosed Turner syndrome, using body surface area in infants, adolescents, obese children and Prader-Willi, adjusting by velocity and change in height SD every 6–12 months and measuring IGF-1 annually; in ISS an IGF-1 of about +1 SD is usual, and consecutive values above +2 SD lead to dose reduction, except in conditions with partial IGF-1 insensitivity (Silver-Russell/SGA, Prader-Willi, IGF1R defects and some girls with Turner), in which they may be necessary for growth [60]. With Norditropin, very short children (< −3 SD) and older pubertal children may start with higher doses (up to 0.067 mg/kg/day), with gradual reduction if catch-up is marked [20].

The 2016 PES guideline on GH and IGF-1, the first in this area developed using the GRADE method, updates that of 2003 and is restricted to GH deficiency, ISS and primary IGF-1 deficiency, because the diagnostic boundary between the three is often blurred; it adds recombinant IGF-1 for the first time [94, 95]. In GH deficiency, it recommends with high-quality evidence GH to normalise adult height and avoid extreme short stature; in ISS, all recommendations are conditional: case-by-case decision through a shared decision-making process that weighs the physical and psychological burden, the risks and the benefits; reassessment of the effect on height and of the psychosocial impact after 12 months of treatment; and a restrained dosing strategy, given the heterogeneity of ISS and the variability of response, including absence of response [95]. The guideline chose adult height as the main outcome, because velocity and short-term change in SD do not reliably predict it, and concluded in favour of more restrictive prescribing than previous guidelines until there is evidence on quality of life and long-term safety [95]. The 2026 Delphi consensus aligns with shared and individualised decision-making, reassessed according to the response, and adds that some children with ISS spontaneously reach normal adult height or a height close to target, that GH may improve the quality of life of children and parents (82% agreement), that an earlier start is associated with a better outcome in some cohorts (in the Kabi/Pfizer international growth database, KIGS, with 4685 children with ISS, a younger prepubertal age at start was associated with a greater gain and higher adult height SD) and that the benefit after the onset of puberty is poorly documented; it does not recommend GnRH analogues or aromatase inhibitors routinely in ISS [70]. The ISS indication was approved by the FDA in 2003 and does not exist at the EMA, so treatment is off-label in many countries [70].

In GH deficiency, the guideline recommends dosing by weight or body surface area and does not take a position on IGF-1-guided dosing, because there are no adult height data with that method; it recommends starting with 0.16–0.24 mg/kg/week (22–35 µg/kg/day) and individualising thereafter; it suggests measuring IGF-1 to assess adherence and response to dose changes and reducing the dose when IGF-1 exceeds the laboratory's normal range for age or pubertal stage (conditional recommendation, very low evidence); it advises against a routine increase to 0.7 mg/kg/week at puberty; and it recommends not continuing paediatric doses after velocity falls below 2–2.5 cm/year, individualising an earlier stop [94]. It advises against, conditionally, routine cardiac examinations, bone densitometry by dual-energy X-ray absorptiometry (DXA) and lipid profile in treated children [94]. In ISS, the 2003 FDA definition (height ≤ −2.25 SD, 1.2nd centile) corresponds in adults to 160 cm in men and 150 cm in women; the guideline advises against routinely treating all children below this threshold, suggests starting with 0.24 mg/kg/week, with some patients needing up to 0.47 mg/kg/week, as there is no clear dose-response relationship, and stopping GH when there is no response; before accepting the ISS label, genetic causes at the growth plate, such as SHOX and NPR2 variants, must be excluded, with assessment of body proportions in all short children [94]. Efficacy is based on three randomised trials to adult height, one of them placebo-controlled, with 237 children (152 treated and 85 controls; 146 followed per protocol to adult or near-adult height), doses of 0.22–0.47 mg/kg/week, 3–7 injections per week and 4.6–6.2 years of treatment: in the systematic review by Deodati and Cianfarani, the gain in treated children exceeded that of controls by 0.79 SD (95% CI 0.50–1.09), about 4.7 cm; in the largest trial, the 68 children without a history of SGA treated per protocol reached −1.5 SD with 0.47 mg/kg/week and −1.7 SD with 0.23 mg/kg/week, against −2.2 SD in controls, many remained below −2 SD and only one exceeded the mean [94]. A meta-analysis of 10 controlled and 28 uncontrolled studies (only 4 to adult height) estimated a mean gain of 4–6 cm (2.3–8.7 cm), about 1 cm per year of treatment [94]. In the only dose study with an untreated group, the difference in gain between 0.23 and 0.47 mg/kg/week was not significant in children with ISS; in another, in 239 children (50 to adult height, without controls), 0.24 mg/kg/week, 0.24 followed by 0.37 mg/kg/week and 0.37 mg/kg/week gave mean gains of 1.55, 1.52 and 1.85 SD, without statistical comparison between groups [94]. Predictors of response have not been validated in controlled studies; in the KIGS models, the height deficit relative to target height, an earlier start (before 10 years in boys and 9 in girls) and the first-year response carry weight [94]. There is no consensus on an adequate first-year response: many studies use an increase of 0.3–0.5 height SD, bearing in mind that healthy children aged 3–8 years may vary by less than 0.3 SD, and published first-year velocity targets for GH exist [94].

Contraindications and warnings (FDA label for Genotropin and Portuguese SmPC): acute critical illness after cardiac or abdominal surgery, multiple trauma or acute respiratory failure (in two intensive care trials in adults without GH deficiency, n = 522, mortality of 42% with 5.3–8 mg/day versus 19% with placebo); Prader-Willi with severe obesity, upper airway obstruction, sleep apnoea or severe respiratory impairment; active neoplasia; closed epiphyses; hypersensitivity; proliferative or severe non-proliferative diabetic retinopathy [18, 101]. The label warns that children with certain rare genetic causes of short stature have an increased risk of neoplasia, so risks and benefits should be weighed and, if treated, they should be monitored; it also describes second neoplasms (meningiomas) in irradiated cancer survivors, unmasking of glucose intolerance or diabetes (especially with obesity, Turner syndrome or a family history), intracranial hypertension (fundoscopy before and periodically), fluid retention, unmasked hypoadrenalism and hypothyroidism, slipped capital femoral epiphysis (assess limping or hip or knee pain), progression of scoliosis and pancreatitis [18]. Lack of response in the first year requires review of adherence, hypothyroidism, malnutrition, advanced bone age and anti-GH antibodies; treatment stops when the epiphyses close [18]. The PES guideline recommends, with high-quality evidence, informing and monitoring all treated patients for intracranial hypertension, slipped capital femoral epiphysis and progression of scoliosis; it recommends reassessing the adrenal and thyroid axes after starting GH when the cause of the deficiency may involve other pituitary deficiencies, monitoring for diabetes in those at increased risk of insulin resistance, and informing about the uncertainty regarding adverse effects after the end of treatment [95]. Monitoring for the three complications is by history and examination at each visit, with additional tests when indicated; reassessment of the adrenal and thyroid axes looks for central insufficiencies not yet diagnosed and leads to consideration of increasing hydrocortisone or levothyroxine already being given [94]. In deficiency acquired after neoplasia, the decision is shared with the oncologist and a 12-month disease-free interval after the end of tumour treatment is reasonable, also in benign tumours with potential for recurrence, such as craniopharyngioma; in conditions with intrinsic cancer risk (neurofibromatosis type 1, Down syndrome, Bloom syndrome, Fanconi anaemia, Noonan syndrome and Diamond-Blackfan anaemia), patients are informed of the lack of evidence on the effect of GH on that risk [94]. In post-marketing surveillance data, adverse effects on treatment occurred in less than 3% of children with GH deficiency or ISS; GH did not increase the incidence of neoplasms in children without risk factors or recurrences after a treated primary tumour, but was associated with an early risk of second neoplasm in irradiated cancer survivors, and data are insufficient for syndromes with baseline cancer risk [95]. Regarding safety after treatment, the French SAGhE study (Safety and Appropriateness of Growth hormone treatments in Europe), in adults treated in childhood for isolated GH deficiency, ISS or SGA, found overall mortality 30% higher than in the general population and more strokes, whereas the cohorts from Belgium, the Netherlands and Sweden found no effect of exposure or dose; the absence of untreated controls and the choice of reference population limit both interpretations [95]. In SGA children, the SmPC recommends fasting insulin and blood glucose before and annually (oral glucose tolerance test if at risk of diabetes; do not administer if diabetic) and IGF-1 before and twice a year, considering the IGF-1/IGFBP-3 ratio if IGF-1 exceeds +2 SD [101].

7.3. Particularities by genetic diagnosis

The supplementary material of the 2026 guideline reviews the clinical consequences of the ten most frequent genetic causes of isolated short stature (ACAN, COL2A1, FBN1, FGFR3, GHSR, IHH, NF1, NPR2, PTPN11, SHOX): GH is registered for two of them (SHOX and PTPN11), and for the rest the data come from short, uncontrolled series, without adult height [1].

The same material lists, in alphabetical order and without claiming to be exhaustive, the genetic causes of short stature with increased cancer risk in which GH is considered contraindicated: ataxia-telangiectasia (Louis-Bar syndrome), Bloom, cartilage-hair hypoplasia, Cockayne, Costello, Dubowitz, Fanconi anaemia, Mulibrey nanism, LIG4 deficiency, neurofibromatosis type 1, Nijmegen, PLK4 deficiency, Rothmund-Thomson, Seckel spectrum, SLF2 and SMC5 deficiencies, xeroderma pigmentosum and XRCC4 deficiency; as GH is registered for short SGA, it is in this group that prior identification of these disorders has the greatest consequence [1]. This list partially diverges from the sources that allow GH with monitoring in neurofibromatosis type 1 with confirmed GH deficiency and that describe a modest benefit in Mulibrey [1, 79].

DNA repair and chromosome breakage disorders: GH is not recommended in Bloom and is contraindicated in Fanconi, Nijmegen, LIG4 and XRCC4; the 2026 guideline therefore recommends genetic testing before GH in SGA children with unexplained short stature and shared decision-making in cases with cancer risk [1, 14]. A persistently raised IGF-1 with a low GH dose should lead to testing of IGF1R and for syndromes such as Bloom or Fanconi [14].

Silver-Russell: GH improves growth velocity, body composition, appetite and the risk of hypoglycaemia; final heights fall short because of the lower starting height; gonadotrophin-releasing hormone (GnRH) analogues for at least 2 years, started by 12 years in girls and 13 in boys, may be considered in central puberty to preserve height [9]. In SGA children in general, a GnRH analogue may be added if the predicted adult height is below −2.5 SD at the onset of puberty [14].

IGF-1 resistance (IGF1R): smaller and more variable response to GH than in SGA, with more insulin resistance; reassess periodically; mecasermin is not indicated, because IGF-1 is already raised [8].

3M: most are assessed for GH deficiency; a small proportion have partial or significant deficiency and others show insensitivity (lack of IGF-1 generation); the response to GH is variable, justifying a therapeutic trial with monitoring of velocity and IGF-1; rhIGF-1 in a CUL7 patient gave a poor response and significant adverse effects [11]. The dysplasia atlas considers that there is no evidence of efficacy [88].

ACAN and NPR2: no specific approved indication; GH is used (in the case of ACAN, sometimes with an aromatase inhibitor or GnRH analogue to delay epiphyseal fusion), within the ISS or SGA indications when applicable or off-label; in a Dutch NPR2 series, the median gain after 2 years was 1.2 SD in prepubertal and 0.5 SD in pubertal children [8].

Hypochondroplasia: mixed results and no adult height data (+1.32 ± 1.05 SD over 3 years in 19 children; +1.9 SD over 6 years in 6 children with p.(Asn540Lys); +0.26 ± 1.19 SD over 4.45 years in 6 children), so GH is considered experimental and controversial [12].

SHORT syndrome: GH may worsen insulin resistance and should be used with caution [82]. Mulibrey: modest benefit of GH [79]. MOPD II and primordial dwarfism: GH ineffective or no data, probably ineffective [14, 75]. Aarskog-Scott: positive effect suggested, without quantitative data in the sources consulted [83].

7.4. Long-acting growth hormone

Somapacitan (Sogroya®) was approved by the FDA in 2020 for adults, on 28-04-2023 for paediatric GH deficiency and on 27-02-2026 for SGA without catch-up by 2 years, Noonan syndrome and idiopathic short stature in children from 2.5 years; the weekly subcutaneous dose is 0.16 mg/kg in GH deficiency and 0.24 mg/kg in the other indications, both by actual weight and individualised according to the growth response, with no maximum paediatric dose defined in the label (the maximum of 8 mg/week applies to adult GH deficiency) [103, 104]. In the EU, Sogroya has been authorised since 31-03-2021 only for GH deficiency (children ≥ 3 years and adults) [105]. Somatrogon (Ngenla®; registered in Brazil as Genryzon®) and lonapegsomatropin (Skytrofa®) are approved in the USA and the EU only for paediatric GH deficiency (somatrogon 0.66 mg/kg weekly from 3 years) [106–110].

7.5. Mecasermin

Mecasermin (recombinant IGF-1, Increlex®) is indicated in the USA (biologics license application, BLA, 021839, first approval in 2005) for children aged 2 years or older with severe primary IGF-1 deficiency or with GH gene deletion and neutralising antibodies, and in the EU (authorised on 02-08-2007) for children and adolescents with severe primary IGF-1 deficiency, including variants of GHR, the post-receptor pathway and IGF1; it does not replace GH and is not indicated in secondary forms [8, 21, 22]. Dose: start 0.04–0.08 mg/kg twice daily subcutaneously, shortly before or after a meal; if well tolerated for at least one week, increase by 0.04 mg/kg per dose up to a maximum of 0.12 mg/kg twice daily; preprandial blood glucose at the start and until the dose is stable [21]. In a long-term open-label study in 76 children with GH insensitivity treated with 60–120 µg/kg twice daily, velocity rose from 2.8 to 8.0 cm/year in the first year and remained above baseline for up to 8 years; adverse effects were frequent but rarely limiting: hypoglycaemia (49%), lipohypertrophy (32%) and tonsillar or adenoidal hypertrophy (22%) [8]. In STAT5B deficiency, the response is lower than in GHR defects (three homozygous siblings: velocity from about 3 to 4.8–7.4 cm/year) [8]. In ALS deficiency, eligibility depends on height reaching −3 SD [8]. The sources consulted found no active registration of mecasermin in Brazil [110]. In the 2016 PES guideline, recombinant IGF-1 to increase height in severe primary IGF-1 deficiency and administration after a meal with education about hypoglycaemia received a strong recommendation with high-quality evidence; unlike GH, which increases insulin resistance, the main risk is hypoglycaemia [94, 95]. The guideline recommends a prior trial of GH when the IGF-1 deficiency is unexplained and allows IGF-1 from the outset in signalling defects without a response to GH: very low or undetectable GHBP and/or a GHR variant associated with Laron syndrome, neutralising anti-GH antibodies (GH1 deletion, type 1A deficiency), STAT5B variants and IGF1 deletion or variant [94]. GH is preferable when it works (partial insensitivity): first-year velocity is 10–12 cm/year in GH deficiency treated with GH and 8–9 cm/year in primary IGF-1 deficiency treated with IGF-1, GH is given as one daily injection instead of two, does not cause hypoglycaemia and also raises IGFBP-3 [94]. The suggested dose is 80–120 µg/kg twice daily (outside the USA 150–180 µg/kg once daily is also used), with a conditional preference for the lower dose: in Ecuadorian patients homozygous for the same GHR variant, 120 µg/kg (n = 14) and 80 µg/kg (n = 7) twice daily gave similar gains in velocity and height SD at 2–3 years, but the high dose accelerated skeletal maturation in the third year, with more body fat and adrenal growth [94]. The guideline dose coincides with the maintenance range of the US label, which starts lower (0.04–0.08 mg/kg) and rises in steps of 0.04 mg/kg up to 0.12 mg/kg twice daily [21, 94]. The only series to adult or near-adult height (bone age ≥ 16 years in boys and ≥ 14 in girls) brought together 21 patients treated for a mean of 10 years (6 with GHR variants, 10 with clinical Laron syndrome and 5 with GH1 deletion and antibodies): velocity rose from 3.1 cm/year to 7.4 cm/year in the first year, 5.6 cm/year in the second and 3.9–5 cm/year in years 3–12; height SD rose by a mean of 1.9 and final height exceeded that expected from the Laron syndrome charts by 13.4 cm, but only 3 patients rose above −2 SD; the study was open-label, uncontrolled, with variable doses and GnRH analogues in 9 patients [94]. IGF-1 is given 20 minutes after a meal or snack containing carbohydrate, the dose is omitted if the child is not going to eat, and monitoring is reinforced, with a home glucometer, during intercurrent illness; hypoglycaemia, described in the label in 42% of patients and sometimes severe (loss of consciousness, seizures), is also a feature of untreated Laron syndrome [94]. The other adverse effects are those of GH (intracranial hypertension, slipped capital femoral epiphysis, progression of scoliosis), tonsillar and adenoidal hypertrophy, hypersensitivity reactions and reactions to the benzyl alcohol in the diluent; active neoplasia contraindicates treatment [94].

7.6. Therapies targeting the growth plate

Vosoritide (Voxzogo®), a C-type natriuretic peptide (CNP) analogue given daily by subcutaneous injection, is approved by the FDA (19-11-2021, with an extension on 20-10-2023) and in the EU (26-08-2021; from 4 months of age, with a confirmed genetic diagnosis) only for achondroplasia with open epiphyses, in the USA by accelerated approval based on annualised growth velocity; before each injection, adequate food and 240–300 mL of fluid in the preceding hour are recommended to reduce hypotension [23, 111]. Navepegritide (Yuviwel®), a weekly sustained-release CNP with dosing by weight bands, was approved by the FDA on 27-02-2026 for achondroplasia from 2 years (accelerated approval) and received a positive opinion from the EMA Committee for Medicinal Products for Human Use (CHMP) on 15-10-2026, with no European Commission decision to date [24, 112]. CNP analogues act on the NPR-B receptor encoded by NPR2, so efficacy cannot be presumed in NPR2 loss of function [8].

7.7. Trials and developments in the last 12 months

These comparisons do not allow conclusions across trials: populations, ages, durations and outcomes differ, and annualised growth velocity at 52 weeks is not equivalent to a gain in adult height, which for CNP analogues is still unknown (hence the accelerated approvals) [23, 24]. Slipped capital femoral epiphysis and genu valgum on vosoritide in diseases other than achondroplasia are safety signals described in small series, without a risk estimate [114, 115]. In the same time window, somapacitan obtained the SGA, Noonan and ISS indications from the FDA (authorisation of 27-02-2026), navepegritide was approved by the FDA (27-02-2026) and received a positive CHMP opinion (15-10-2026), and the international genetic testing guideline, the systematic review of yield, the Delphi consensus on ISS and the Italian consensus were published [1, 15, 24, 70, 96, 103, 112]. In preclinical research, infigratinib proved to be a weak inhibitor of the hypochondroplasia FGFR3 p.(Asn540Lys) mutant [117].

7.8. Non-pharmacological interventions

In skeletal dysplasias, limb alignment surgery aims to preserve the joints and function; surgical limb lengthening, used for more than 15 years in achondroplasia and hypochondroplasia, has decreasing complications but is invasive and prolonged, and many paediatricians, geneticists and ethicists advocate postponing it until adolescence, when the person can decide for themselves [12, 87]. Physiotherapy and occupational therapy support activities of daily living [87]. Specific treatments for syndromic causes: pericardiectomy in the constrictive pericarditis of Mulibrey (benefit in about two thirds); calcitriol and calcium in Kenny-Caffey; levothyroxine, pancreatic enzymes and fat-soluble vitamins in Johanson-Blizzard; glucocorticoid replacement in the adrenal insufficiency of IMAGe [79–81, 85]. In SGA children, nutrition should ensure catch-up without excessive weight gain (change in weight-for-length > 0.67 SD), and additional supplementation is not recommended in healthy infants up to 6 months [14].

7.9. Agents and circumstances to avoid; perioperative care

Prolonged fasting in infants and young children with Silver-Russell (hypoglycaemia) and GH tests with fasting; unnecessary elective surgery, with attention to hypoglycaemia, hypothermia, wound healing and difficult intubation [9]. Difficult intubation and airway obstruction in Hallermann-Streiff [91]. Cervical spine radiographs in flexion and extension before anaesthesia in dysplasias with odontoid hypoplasia [87]. Somatropin in DNA repair disorders and in acute critical illness [14, 18].

7.10. Pregnancy, transition and end of treatment

In hypochondroplasia, vaginal delivery is possible, assessing pelvic capacity against the size of the fetal head in each pregnancy, and neuraxial anaesthesia requires a prior anaesthetic consultation [12]. In SGA children, GH ends when velocity is less than 1 cm per 6 months with closed epiphyses, or in the face of repeated non-adherence or lack of response; interruption after 3 years of good response causes loss of height and is not recommended; after treatment, adults should maintain a healthy lifestyle, with metabolic follow-up if they have risk factors [14]. In Turner syndrome, GH may continue until bone age ≥ 14 years and/or velocity < 2 cm/year [17]. In the European SmPC for Genotropin, treatment in SGA is stopped with velocity < 2 cm/year and bone age > 14 years (girls) or > 16 years (boys) [101]. In GH deficiency, the 2016 PES guideline continues paediatric doses only until velocity falls below 2–2.5 cm/year and classifies as persistent deficiency, without retesting, patients with three or more pituitary deficiencies, with a documented genetic cause or with a structural hypothalamic-pituitary defect (except ectopic posterior pituitary); in the rest (idiopathic isolated deficiency, a single additional deficiency, small pituitary or ectopic posterior pituitary, irradiation), the axis is reassessed after at least 1 month off GH, starting with IGF-1 and performing a stimulation test if it is low [94]. In the insulin tolerance test, a threshold of 5.6 µg/L (immunometric assay) had a sensitivity of 77% and specificity of 93% for persistent deficiency; a normal IGF-1 does not obviate the test in multiple deficiencies [94]. GH is offered at transition to those with persistent deficiency: three randomised trials showed an increase in bone mineral density and lipid improvement with 2 years of treatment and a fourth did not, and the optimal dose is uncertain (12.5–25 µg/kg/day or 200 µg/day in the trials) [94].

7.11. Guideline recommendations and divergences

The main divergences are: the definition of short stature (−2 SD and dynamic criteria in the 2026 guideline and the Delphi consensus; 0.4th centile in clinical genetics texts) [1, 4, 70]; the nomenclature of short stature without a cause (ISS, isolated idiopathic short stature, healthy short stature) [1–3]; the age and thresholds for GH in SGA (2–4 years in the USA; ≥ 4 years and −2.5 SD in the EU; 3–4 years in the 2023 consensus) [14, 18, 100]; the ISS indication, present in the USA and absent in the EU [18, 100]; the dose in SGA (titration up to 0.067 mg/kg/day in the consensus; 0.035 mg/kg/day in the SmPC) [14, 101]; and who requests the Turner karyotype (any paediatrician, according to part of the Italian panel; a specialist centre, according to others) [15]. In addition: the threshold for disproportion (±2 SD in the Delphi consensus; ±2.5 SD in the genetic testing guideline) [1, 70]; the place of SGA and CDGP (groups excluded from ISS in the Delphi consensus; in the 2026 guideline, isolated idiopathic short SGA is a subcategory parallel to isolated idiopathic short stature) [1, 70]; laboratory screening (a systematic minimum in the Delphi consensus and the Italian consensus; clinically guided in GRS 2019) [15, 60, 70]; the height threshold for treating ISS (−2 SD in the Delphi consensus definition; ≤ −2.25 SD in the US label) [18, 70]; pubertal modulation (not routinely recommended in ISS by the Delphi consensus; allowed in SGA with predicted adult height below −2.5 SD at the onset of puberty) [14, 70]; and the list of oncological contraindications to GH, which in the supplementary material of the 2026 guideline includes neurofibromatosis type 1 and Mulibrey nanism, accepted with caution in other sources [1, 79]. The 2016 PES guideline is more restrictive in ISS than the US labels: it advises against routinely treating all children below −2.25 SD and requires reassessment at 12 months, although the maximum dose (0.47 mg/kg/week) coincides with that of Genotropin, Norditropin and Omnitrope [18, 94, 95]. Regarding the stimulation test, the 2016 PES guideline sets no threshold and documents the low specificity of the 10 µg/L threshold, GRS 2019 indicates an assay-dependent 7 ng/mL and the Delphi consensus allows 7.5–10 µg/L [60, 70, 94]. Regarding mecasermin, the guideline suggests 80–120 µg/kg twice daily with a preference for the lower dose, the US label starts at 0.04–0.08 mg/kg and rises to 0.12 mg/kg twice daily, and outside the USA a single daily dose of 150–180 µg/kg is also used [21, 94].

8. Reproductive Options and Family Counselling

8.1. Pre-test and post-test counselling

The 2026 guideline recommends genetic counselling for all families undergoing testing and a pre-test consultation discussing benefits (diagnosis, prognosis, therapeutic guidance, family testing) and risks (false positives, VUS, secondary findings, insurance implications) [1]. In children, diagnostic variant testing is only justified when it offers a potential health benefit for the child, always preceded by counselling [1].

8.2. Recurrence risk by scenario

8.3. Family testing and cascade testing

Testing relatives is useful when the same variant influences management or counselling, and segregation may reclassify a VUS, with the caution imposed by incomplete penetrance and variable expressivity [1]. In SHOX deficiency, testing siblings allows early identification of those who benefit from GH, and in large families testing identifies unrecognised carriers [4, 7]. In Kenny-Caffey, the dominant transmission described is mainly maternal, probably because of male infertility [85]. Target height is only interpretable when the parents do not themselves have a genetic cause of short stature, which reinforces the value of measuring and examining the parents [4].

8.4. Prenatal and preimplantation diagnosis

With an identified variant, prenatal diagnosis (chorionic villus sampling, amniocentesis) or preimplantation diagnosis; serial ultrasound scans complement monitoring of fetal growth, but restriction is rarely detectable before 28 weeks and the prediction of dysplasias at 20 weeks has pitfalls [4, 13, 87]. In imprinting conditions, a prenatal result does not reliably predict severity, and 11p15 loss of methylation cannot be tested reliably prenatally [9]. In Turner syndrome diagnosed prenatally, fetal echocardiography and confirmation by postnatal karyotype are recommended [17].

8.5. Counselling of minors and psychosocial dimension

Children with body differences or short stature are often sensitive about body image, with an impact on peer relationships and socialisation, which justifies early referral and psychological support [9, 87]. Irreversible decisions, such as surgical limb lengthening, should be postponed, according to many experts, until the adolescent can take part in an informed way [12]. In hypochondroplasia, GeneReviews recommends addressing the parents' expectations and preconceptions about height rather than trying to treat the child [12].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the figures measure

By statistical definition, about 2.3% of children in any population have a height below −2 SD [1]. The Utah Growth Study (USA), which measured 114,881 school-age children and calculated 79,495 growth velocities, examined 555 children below the 3rd centile with a velocity below 5 cm/year: 5% had endocrine disease, most slowly growing children had no endocrine disease, the minimum prevalence of GH deficiency was 1:3480 (boys:girls 2.7:1), 48% of GH deficiencies had not been recognised and six girls with Turner syndrome were identified [118]. The aetiological proportions of the Oxford Desk Reference (75% familial or constitutional, 10% chronic disease, 6% syndromes, 5% chromosomal, 1% dysplasias, 1–2% GH deficiency or insensitivity) describe referred children, without a declared population denominator [4]. The diagnostic yields of Section 5.10 measure the proportion of diagnoses in cohorts selected for testing, not the prevalence of the disorders [96].

9.2. Frequency of the main entities

9.3. Geography, founder populations and growth standards

Growth charts should be national or those most suitable for the population; classic anthropometric norms derive mainly from white populations and the upper/lower segment ratio is systematically lower in black children [14, 93]. In low- and middle-income countries, only 50–60% of SGA children catch up, because of maternal and postnatal malnutrition, infections and socioeconomic conditions, and catch-up may be delayed until 4–5 years, which changes the age from which persistent short stature suggests an intrinsic cause [14]. Examples of founder populations in the sources consulted: Mulibrey nanism in Finland, Bloom syndrome in Ashkenazi Jews [14, 79]. In China, ACAN accounted for about 1.2% of more than 1000 unselected short children, 14.3% of those with advanced bone age and 35.7% with advanced bone age and a family history; a 2023 Chinese consensus recommends genetic testing in ISS, especially below −3 SD or with familial short stature [8, 73]. The Brazilian and Pakistani forms of GH deficiency due to GHRHR (Itabaianinha, Sindh) are founder forms of isolated GH deficiency. The proposal of "healthy short stature" comes from Brazilian authors [3]. The sources consulted do not present epidemiological data specific to Portugal.

9.4. Access to treatments by jurisdiction

In the USA, somatropin has indications for ISS, SHOX deficiency and Noonan, and since February 2026 weekly somapacitan covers SGA, Noonan and ISS [18, 19, 103]. In the EU (and in Portugal), the paediatric indications for somatropin are GH deficiency, Turner, chronic kidney disease, SGA with more restrictive criteria and Prader-Willi, plus Noonan for Norditropin; long-acting GH preparations are limited to GH deficiency [100–102, 105]. In Brazil, the ANVISA open database lists as active several somatropin products (Genotropin, Norditropin, Omnitrope, Saizen, Eutropin, Biomatrop, Criscy, Hormotrop and somatropin from Bio-Manguinhos/Fiocruz), somatrogon (Genryzon), somapacitan (Sogroya) and vosoritide (Voxzogo); no active registration of mecasermin was found, and the indications in the Brazilian package leaflets were not consulted [110].

9.5. Special populations

Children born very preterm or with severe SGA need closer monitoring and early referral [14]. Children with obesity and short stature deserve investigation, because overweight children tend to be tall [4]. In girls, short stature may be the only sign of Turner syndrome [1, 17].

9.6. European Reference Networks and patient associations

Endo-ERN (European Reference Network for rare endocrine conditions, with more than 100 centres in 27 Member States and Norway) organises this area in the thematic group MTG5 "Growth & Genetic Obesity Syndromes" (imprinting disorders such as Silver-Russell, GH and IGF-1 insensitivity, Noonan, restriction and overgrowth syndromes) and in MTG6 (hypothalamic-pituitary conditions) [25]. Skeletal dysplasias are in ERN BOND and malformation syndromes with intellectual disability in ERN ITHACA [26, 27]. Associations: MAGIC Foundation (USA), Little People of America, Child Growth Foundation and Restricted Growth Association (United Kingdom) and ANDO Portugal — Associação Nacional de Displasias Ósseas (National Association of Skeletal Dysplasias), with branches in the Azores and Madeira and a project aimed at Portuguese-speaking African countries [4, 87, 119].

10. Illustrative Clinical Case

10.1. "Familial" short stature with a monogenic cause

Zhang and colleagues (Beijing Children's Hospital, 2026) described a 3-year-old boy, the first child of non-consanguineous parents, born by caesarean section at 38 weeks because of maternal short stature, with a weight of 2.9 kg (−1.19 SD) and a length of 48 cm (−1.43 SD) [73]. Motor and cognitive development were normal; in the first year he grew about 22 cm, reaching 70 cm (−2.48 SD). He was assessed for persistent short stature and deceleration; the mother reported psychosocial distress because of her short stature and asked for early intervention [73]. On examination he measured 89 cm (−2.1 SD) and weighed 13.8 kg (−1.32 SD), without dysmorphic features, with normal proportions (arm span 87 cm; upper/lower segment ratio 1.25) and without rhizomelic shortening (Figure 1A, https://pmc.ncbi.nlm.nih.gov/articles/PMC13581500/figure/f1/) [73].

The family history showed short stature on the maternal side: mother 134 cm (−4.91 SD), menarche at 10 years, when she already measured about 130 cm, never treated for lack of access; maternal grandmother 140 cm (−3.8 SD); maternal grandfather 148 cm (−4.06 SD); father 170 cm (−0.44 SD) and paternal grandparents 155 and 170 cm [73]. Full blood count, electrolytes, liver, renal and thyroid function, and 08:00 cortisol and ACTH were normal; IGF-1 112 ng/mL (+0.37 SD); karyotype 46,XY; pituitary MRI and abdominal ultrasound normal; the spinal radiograph, reviewed by a paediatric radiologist experienced in dysplasias, showed only mild scoliosis, and bone age was concordant with chronological age (Figure 1B–F) [73].

Trio exome sequencing identified the heterozygous variant FGFR3 NM_000142.5:c.1619A>G p.(Asn540Ser), inherited from the mother and present in the maternal grandfather, absent in the father, the paternal grandparents and the maternal grandmother, classified as likely pathogenic (ACMG criteria PS1, PM2, PP1 and PP4) (Figure 2, chromatograms and pedigree, https://pmc.ncbi.nlm.nih.gov/articles/PMC13581500/figure/f2/) [73, 74]. All previous cases with this variant had a hypochondroplasia phenotype; this family was the first described with proportionate short stature, without radiological changes, over three generations [73]. After family counselling, the child started somatropin (dose not stated in the article); at 9 months he measured 97 cm (−0.92 SD), with normal thyroid function and glycated haemoglobin and an IGF-1 of 124 ng/mL (+0.49 SD); follow-up continues, with monitoring for signs of hypochondroplasia [73].

10.2. Reading the case in the light of the approach

The case meets several of the 2026 guideline criteria for genetic testing: a family history compatible with dominant inheritance, a mother with height below −3 SD and a child shorter than the mid-parental height, even though the child is only slightly below −2 SD [1]. A target height calculated from an affected mother would be misleading, because it includes the effect of the variant [4]. Trio exome sequencing, with segregation analysis, was the technique that clarified the cause, and FGFR3 is on the minimum list of genes recommended for isolated short stature [1]. The therapeutic approach in the report does not correspond to established practice in the European and North American guidelines: GH in hypochondroplasia is considered experimental and controversial, without adult height data, vosoritide is approved only for achondroplasia, and the result at 9 months does not allow final height to be inferred [12, 23, 73, 111]. The authors state that GH is approved for ISS in the USA and for achondroplasia and hypochondroplasia in Japan [73].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis depends on the cause. Familial short stature and constitutional delay lead to an adult height close to target height [1, 4]. In monogenic and chromosomal causes, untreated adult heights range from slightly below normal (Noonan, Aarskog-Scott, KBG) to severely reduced (3M 115–150 cm; MOPD II < 100–110 cm; Turner 138–147 cm) (Section 3.2) [10, 17, 77, 78, 83, 90]. Life expectancy and quality of life depend mainly on comorbidities: cancer risk in DNA repair disorders and Mulibrey, heart disease in Noonan and Mulibrey, cerebral vasculopathy in MOPD II, diabetes in SHORT, MOPD II and Mulibrey, early osteoarthritis with ACAN, vertebral complications in dysplasias [8, 10, 14, 77, 79, 82, 87]. In 3M the overall prognosis is good, with few complications described [88].

11.2. Surveillance

Entity-specific surveillance (cardiological in Noonan and Turner, oncological in DNA repair disorders, orthopaedic in dysplasias) is in addition to this.

11.3. Transition

In persistent GH deficiency, GH continues after growth has ended to complete lean mass and peak bone mass [101, 102]. The criteria for persistent deficiency without retesting, reassessment after at least 1 month off GH and the thresholds of the insulin tolerance test at transition are given in Section 7.10 [94]. In treated SGA children, metabolic and cardiovascular follow-up in adulthood is recommended when there are risk factors, as are national and international long-term health registries [14]. In skeletal dysplasias, medical supervision usually extends into adulthood [87].

12. Summary and Final Considerations

Short stature is a sign with multiple causes, and most referred children have a normal variant of growth, of polygenic or maturational origin. Clinical reasoning is based on rigorous auxology (height, velocity, target height, proportions and head circumference), on the distinction between prenatal and postnatal onset and on the exclusion of treatable secondary disorders by laboratory screening, including IgA anti-transglutaminase 2 and thyroid function, and by bone age. In all girls with unexplained short stature, Turner syndrome is sought by karyotype with at least 30 metaphases or another validated method.

The 2026 international guideline organises the genetic step into four categories — isolated short stature, suspected skeletal dysplasia, suspected GH/IGF-1 axis defect and syndromic short stature — and defines when to test: height below −3 SD, microcephaly, relative macrocephaly, disproportion, dysmorphic features, malformations, neurodevelopmental disorder, skeletal anomalies, apparent Mendelian inheritance, a child much shorter than both parents and short SGA who are candidates for GH. In isolated short stature with suspected constitutional delay or polygenic origin, testing is not indicated. Exome with copy number variant analysis or the genome are the first-line techniques in most categories, with exceptions: 11p15/7/14q32 methylation when imprinting is suspected, MLPA of SHOX and the PAR1 region, and a targeted panel in GH insensitivity. The exome yield is about 15% in isolated short stature, 50% in syndromic short stature and 70% in suspected dysplasia, and a negative result justifies periodic reanalysis.

The genetic diagnosis changes management: it identifies approved indications for somatropin (Turner, SHOX, Noonan, Prader-Willi, SGA, GH deficiency and, in the USA, idiopathic short stature), primary IGF-1 deficiency treatable with mecasermin, DNA repair disorders in which GH should not be used and conditions in which the response is poor (primordial dwarfism, 3M, IGF1R, dysplasias). Indications and doses differ between the USA and the EU, and the guidelines serve as the reference where they diverge from the labels. Therapies targeting the growth plate (C-type natriuretic peptide analogues, FGFR inhibitors) are approved only in achondroplasia, with phase 2 and 3 results in hypochondroplasia, RASopathies, ACAN and NPR2 and orthopaedic safety signals described in small series. Follow-up integrates auxological surveillance, treatment monitoring and the comorbidities of each entity, in coordination with the European Reference Networks Endo-ERN, ERN BOND and ERN ITHACA.

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