Growth hormone therapy in Turner syndrome: Do cytogenetic subtypes influence outcomes?

Abstract

Turner syndrome (TS) is a chromosomal disorder caused by complete or partial loss of one X chromosome, occurring in approximately 1 in 2500 live female births. Short stature, resulting from haploinsufficiency of the short stature homeobox-containing (SHOX) gene, absence of a pubertal growth spurt, and ovarian insufficiency are hallmark features. Recombinant human growth hormone (GH) therapy remains the mainstay of management, increasing adult height by approximately 5–8 cm. This review examines how cytogenetic subtypes influence GH response, focusing on 45,X monosomy, mosaicism, and structural abnormalities such as isochromosome Xq and ring X. Patients with 45,X monosomy often show a favorable initial response but a more rapid decline in growth velocity, whereas mosaic patients maintain better long-term outcomes. Structural variants involving Xp loss exhibit similarly attenuated responses. Overall, differences between cytogenetic subtypes tend to diminish over time, with age at therapy initiation, treatment duration, and timing of pubertal induction exerting a greater influence on final height outcomes.

Resumen

El síndrome de Turner (ST) es un trastorno cromosómico causado por la pérdida completa o parcial de un cromosoma X, que ocurre en aproximadamente 1 de cada 2.500 nacimientos femeninos vivos. La baja estatura, debida a la haploinsuficiencia del gen SHOX (short stature homeobox-containing), la ausencia del brote puberal de crecimiento y la insuficiencia ovárica son características distintivas. La terapia con hormona de crecimiento humana recombinante (GH) sigue siendo el pilar del tratamiento, aumentando la talla adulta en promedio entre 5 y 8 cm. Esta revisión analiza cómo los subtipos citogenéticos influyen en la respuesta a la GH, centrándose en la monosomía 45,X, el mosaicismo y las anomalías estructurales como el isocromosoma Xq y el cromosoma en anillo X. Las diferencias entre subtipos tienden a disminuir con el tiempo, siendo la edad al inicio de la terapia, la duración del tratamiento y la inducción puberal los factores con mayor influencia sobre la talla final.

Introduction

Turner syndrome (TS) is a chromosomal disorder that arises when one X chromosome is completely or partially absent in females. It represents the only monosomy compatible with life in humans and is among the most frequent chromosomal abnormalities, occurring in approximately 1 in 2500 live female births. The clinical features of TS were first described by Turner in 1938, and the chromosomal basis of X monosomy was established in 1959. Classic monosomy 45,X is found in approximately 45% of cases, whereas the remaining patients present with mosaicism or structural abnormalities of the X chromosome.^1–4

The clinical spectrum of TS is wide and may include upper and lower extremity lymphedema, a short webbed neck, a low posterior hairline, cubitus valgus, and hypoplastic or hyperconvex nails. Additional features include micrognathia, a high-arched palate, short stature, gonadal dysgenesis, primary amenorrhea, sexual infantilism, and infertility. Patients may also present with a shield-shaped chest and widely spaced areolae. TS is associated with congenital heart defects, such as coarctation of the aorta and ventricular septal defects, as well as renal malformations, including horseshoe kidney, urethral duplication, or unilateral renal agenesis.⁵

Additionally, affected individuals may present with multiple pigmented nevi, scoliosis, and hypoplasia of the fourth or fifth metacarpal or metatarsal bones. Beyond these classical features, females with TS may also present with hearing impairment, arterial hypertension, osteoporosis, obesity, visual impairment, impaired glucose tolerance, learning difficulties, and psychosocial challenges.^6,7

TS is diagnosed in females with complete or partial loss of one X chromosome, typically involving the short arm, together with characteristic clinical features. The recommended diagnostic approach is a 30-cell karyotype, which can detect mosaicism of 10% or greater with 95% confidence. If clinical suspicion persists despite a normal result, further metaphase analysis or evaluation of additional tissues, such as skin fibroblasts or buccal cells, may be required.^8,9

Prenatal detection is possible through invasive procedures such as amniocentesis or chorionic villus sampling; however, confirmation by postnatal karyotype is required because of the risk of false-positive results. Ultrasound findings that increase diagnostic specificity include increased nuchal translucency, cystic hygroma (present in 30–70% of cases), left-sided cardiac malformations such as coarctation of the aorta, renal anomalies, oligohydramnios, and polyhydramnios. In these cases, genetic counseling is essential to provide families with accurate information regarding prognosis, associated comorbidities, and long-term quality of life.^10,11

This aneuploidy most commonly results from a nondisjunction event, affecting the paternal genome in approximately 60–80% of cases. Approximately 50–60% of patients exhibit complete monosomy X (45,X), defined by the absence of the second sex chromosome. Mosaicism, involving two or more distinct cell lines derived from the same zygote, occurs in approximately 20–40% of cases. In some instances, mosaicism may be confined to tissues other than peripheral blood, complicating diagnosis unless the affected tissue is specifically analyzed.¹²

Structural abnormalities of the X chromosome are observed in approximately 10% of cases, with isochromosome of the long arm being the most frequent. Additional alterations include ring chromosomes and deletions of both the short and long arms. Furthermore, 3–5% of patients present cell lines containing a 46,XY complement or Y chromosome-derived marker sequences.¹³

Genes implicated in TS are primarily located on the short arm of the X chromosome and typically escape X inactivation, allowing biallelic expression.¹⁴ X-chromosome methylation is the key mechanism responsible for silencing one allele and maintaining normal gene dosage.^15,16 In 45,X cells, the absence of a second sex chromosome disrupts this balance, leading to haploinsufficiency of genes on the short arm of the X chromosome. Several of these genes have been mapped to regions associated with characteristic clinical features of TS, including loci related to short stature (Xp11.2–p22.1), ovarian function (Xq13–q16), and lymphatic development (pseudoautosomal regions of Xp and Yp).¹⁷

Short stature is a hallmark feature of Turner syndrome. In the absence of treatment, affected girls are, on average, 20 cm shorter than their healthy peers within the same population.¹² Beyond reduced height, their growth trajectory is distinct, primarily due to haploinsufficiency of the short stature homeobox-containing (SHOX) gene on the X chromosome and the effects of ovarian insufficiency. Treatment with growth hormone (GH) has been shown to accelerate growth velocity and significantly improve final adult height.¹⁸

In this review, we aim to explore whether the various cytogenetic subtypes of Turner syndrome – classic monosomy 45,X, mosaic forms, and X-chromosome structural abnormalities – differ in their response to growth hormone therapy and whether genotype-phenotype correlations influence treatment outcomes and final adult height.

Cytogenetic subtypes of Turner syndrome

The karyotypic spectrum of Turner syndrome encompasses both aneuploidies and structural abnormalities of the X chromosome. Aneuploid forms include monosomy 45,X (40–50% of cases), mosaicism with 45,X/46,XX (15–25%), 45,X/46,XY (3–10%), and 45,X/47,XXX (approximately 3%). Structural variants include isochromosome Xq [46,X,i(Xq) or 45,X/46,X,i(Xq) mosaicism] in approximately 10% of cases, ring chromosome mosaicism [45,X/46,X,r(X)] in approximately 7%, and, less frequently, deletions of the Xp or Xq arms.^19,20

Although karyotype does not consistently predict phenotype in Turner syndrome, several trends have been identified across cytogenetic subgroups. Individuals with a 45,X karyotype typically present with a more severe phenotype, whereas those with 45,X/46,XX mosaicism often exhibit milder clinical features, including less pronounced dysmorphism, fewer cardiovascular and lymphatic anomalies, and, in some cases, partial preservation of ovarian function with the possibility of spontaneous pregnancy. However, mosaicism also carries an increased risk of miscarriage and premature ovarian failure compared with the general population.^21–23 The presence of Y chromosome material is associated with an increased risk of gonadoblastoma, estimated at approximately 10%, prompting recommendations for prophylactic gonadectomy.^24,25 When conventional fluorescence in situ hybridization (FISH) fails to detect Y chromosome material in virilized patients, molecular screening for cryptic Y sequences is warranted.²⁶ Ring X chromosomes may also be associated with intellectual disability of variable severity.^27,28 These observations highlight that distinct karyotypic patterns are associated with variable clinical expression, raising the question of whether cytogenetic heterogeneity may also influence growth trajectory and response to growth hormone therapy in this population.

Short stature in Turner syndrome

One of the hallmark features of Turner syndrome (TS) is short stature. Untreated girls with TS are, on average, approximately 20 cm shorter than females in the general population, reflecting impaired growth both prenatally and postnatally.²⁹

The cytogenetic subtypes of TS reflect distinct molecular mechanisms of gene dosage imbalance, particularly involving Xp-located genes such as SHOX, which directly modulate chondrocyte proliferation and GH sensitivity at the growth plate (Fig. 1).

Figure 1.

Growth hormone signaling and the molecular impact of SHOX haploinsufficiency on linear growth. This figure illustrates, in the upper panel, physiological GH signaling, where GH binds to the GHR and activates the JAK2–signal transducer and STAT5 pathway, promoting IGF-1 synthesis and normal growth velocity.³⁵ In the lower panel, SHOX haploinsufficiency disrupts the regulation of several downstream genes within the growth plate. Reduced SHOX activity leads to upregulated FGFR3 expression, which inhibits chondrocyte proliferation; premature activation of RUNX2, accelerating chondrocyte hypertrophy and ossification; loss of regulatory synergy with SOX9, causing extracellular matrix disorganization; and decreased NPPB expression, diminishing chondrocyte proliferation and columnar organization.³⁶ Together, these molecular alterations impair endochondral ossification, leading to reduced bone growth and short stature characteristic of SHOX deficiency and Turner syndrome (created with BioRender.com). Abbreviations: GH, growth hormone; GHR, growth hormone receptor; JAK2, Janus kinase 2; STAT5, signal transducer and activator of transcription 5; IGF-1, insulin-like growth factor 1; FGFR3, fibroblast growth factor receptor 3; RUNX2, runt-related transcription factor 2; SOX9, SRY-box transcription factor 9; NPPB, natriuretic peptide B.

This genetic mechanism also accounts for several additional phenotypic features commonly observed in TS, including a high-arched palate, obstructive sleep apnea, prominent ears, and recurrent otitis media.³⁰ Although affected individuals do not have classic growth hormone deficiency, they respond favorably to growth hormone therapy, similar to patients with isolated SHOX deficiency,³¹ with an average height gain of approximately 7 cm. The magnitude of benefit is influenced by both the age at treatment initiation and the overall duration of therapy.³² Findings from a French multicenter observational study further demonstrated that karyotype subgroups are associated with variations in spontaneous intrauterine growth, postnatal growth, and adult height achieved following GH therapy.³³ The authors proposed that haploinsufficiency of an as-yet-unidentified gene on Xp may increase the risk of impaired prenatal and postnatal growth and reduced adult height despite GH treatment.³⁴

In addition to SHOX haploinsufficiency, ovarian insufficiency is also a key determinant. The lack of endogenous estrogen secretion leads to the absence of a pubertal growth spurt, thereby further accentuating the height deficit compared with the general population. Although girls with TS do not have classic growth hormone deficiency, their response to growth hormone therapy is similar to that of patients with isolated SHOX deficiency, suggesting a shared regulatory pathway in growth.

Growth curves in TS are characterized by slightly reduced birth weight and length, a sharp decline in growth velocity during the first 2 years of life, and a slower but persistent decline until the expected age of puberty. At the stage when typically developing children experience a pubertal growth spurt, girls with TS fail to do so because of estrogen deficiency, resulting in a widening gap in height. After puberty, growth velocity may increase slightly due to delayed epiphyseal closure; however, this is insufficient to compensate for the lack of pubertal growth. Consequently, the average adult height in untreated TS is approximately 20 cm below population norms, corresponding to a height standard deviation score (SDS) of −2.5 to −4.1.³⁷

Furthermore, longitudinal observational studies show that TS-specific 5th percentile growth charts differ significantly from those of the general population and are essential for accurate monitoring. These charts demonstrate that most girls with TS fall below the 5th percentile for height by age 5 years. They also illustrate the secular trend: as in the general population, adult height in TS has increased slightly over recent decades, although the relative deficit compared with peers remains unchanged.^38–40

Recombinant growth hormone treatment

Recombinant human GH (hGH) therapy is now routinely used to treat growth impairment in girls with TS. It is estimated to increase adult height by approximately 5–8 cm at doses of 42–50 mg/kg/day. Earlier initiation and adequate duration before puberty enhance efficacy, with at least 4 years of treatment before puberty associated with improved outcomes. Monitoring with TS-specific growth charts is essential, and management should balance GH therapy with timely pubertal induction.^{18,20,41–45}

Haploinsufficiency of SHOX is the primary determinant of short stature in girls with TS, leading to reduced sensitivity to GH and necessitating the use of higher doses of recombinant human GH (rhGH) compared with GH-deficient patients. Most guidelines recommend initiating therapy between ages 4 and 6 years.^46–50

While the primary goal of rhGH treatment is to improve final adult height, accumulating evidence highlights additional long-term benefits beyond growth promotion. GH exerts multiple metabolic effects both directly and through insulin-like growth factor 1 (IGF-1), insulin, and free fatty acids. These include improved body composition, increased muscle and bone mass, promotion of peak bone mass, and regulation of protein, lipid, and carbohydrate metabolism.^51–53

Clinical studies in GH-deficient children have shown that long-term rhGH therapy improves body composition, may transiently affect glucose metabolism, and can positively influence lipid profiles.^54–59 In TS, rhGH therapy has been associated with reduced adipose tissue, increased lean body mass, and improved lipid profiles, although data on long-term persistence after treatment discontinuation remain limited.^37,60–62 Some studies suggest a slightly increased risk of insulin resistance, underscoring the importance of metabolic monitoring, particularly given the elevated cardiovascular risk in TS.^63–68

Cardiac safety is also an important consideration. While rhGH therapy has been associated with a reduced risk of ischemic heart disease, some authors suggest a possible association with aortic dilatation, necessitating regular IGF-1 monitoring and echocardiographic follow-up.^69,70

Regarding bone density, most studies and meta-analyses do not demonstrate significant improvements in bone mineral density (BMD) with rhGH monotherapy.^{20,61,71–78} However, combined treatment with rhGH and estrogen replacement appears to reduce the risk of osteoporosis.^79,80 Additional benefits include positive effects on craniofacial development (notably mandibular ramus and posterior facial height),^81,82 uterine size before estrogen therapy, and overall muscle mass.^83,84 RhGH therapy has also been associated with improvements in quality of life (QoL), contributing to increased self-confidence, better social integration, and improved educational outcomes extending into adulthood.

However, some authors note that QoL benefits may be less pronounced in the absence of timely estrogen replacement.^85–92

Improved adult height outcomes in females with TS are associated with greater parental height, taller stature at treatment initiation, better first-year growth response to hGH, higher mean weekly hGH dose, and younger age at onset of puberty.^93–101

Jung Min Ahn et al. found that early initiation of growth hormone therapy in Turner syndrome significantly improves final adult height outcomes. Specifically, GH-treated girls with TS attained a mean final height of approximately 152 cm (approximately −1.9 SDS), about 12.2 cm above their projected height at treatment initiation, whereas untreated girls with TS reached approximately 143.6 cm (approximately 3.9 cm above baseline projections). Final adult height was positively correlated with the height SDS at the start of GH treatment. Notably, patients who achieved a normal-range adult height after GH therapy had a higher baseline height SDS and higher mid-parental height SDS and tended to begin estrogen replacement at a younger age.¹⁰² Most studies indicate that combining estrogen therapy with hGH maximizes final height outcomes in girls with Turner syndrome. Current evidence supports initiating estrogen replacement at a typical pubertal age (approximately 12 years), rather than delaying treatment until 15 years.^{98,99,101,103} The earlier belief that delaying estrogen therapy improved height potential was likely influenced by older protocols that introduced high doses of conjugated estrogens at a younger age, which suppressed growth despite the biphasic effect of estradiol: stimulation at low doses and inhibition at higher levels.¹⁰⁴ A pivotal 20-year trial demonstrated that initiating very low doses of estradiol at pubertal age, titrated gradually to mimic physiologic puberty, significantly enhanced adult height when combined with hGH.¹⁰⁵ Beyond height, timely initiation of estradiol at approximately 12 years also supports normal bone mass accrual¹⁰⁶ and reduces psychosocial risks associated with delayed puberty, such as poor self-image.^88,101

Cytogenetic subtypes and response to GH treatment

45,X karyotype

The 45,X karyotype is the most common chromosomal constitution in Turner syndrome, occurring in approximately 40–50% of patients.⁴⁷ It has been observed in 1–2% of human conceptions, 10% of first-trimester pregnancy losses, and 1% of stillbirths. More than 99% of 45,X fetuses result in spontaneous abortion, typically by the 28th week of gestation, suggesting that surviving 45,X individuals likely have mosaicism for another cell line.^107,108 The etiology includes preconceptional errors, as well as meiotic nondisjunction and anaphase lag.¹⁰⁹

Compared with mosaic or structural variants, individuals with 45,X generally exhibit the most severe clinical phenotype and carry the highest risk of morbidity and mortality.¹¹⁰

The severe phenotype observed in 45,X is thought to reflect the consequences of haploinsufficiency of genes located in the pseudoautosomal region 1 (PAR1) – notably the SHOX gene, which is essential for normal skeletal growth – as well as other X-Y gene pairs and genes that escape X-chromosome inactivation. These genetic mechanisms likely contribute to short stature, gonadal dysgenesis, lymphedema, and skeletal abnormalities characteristic of this karyotype.^111,112

Anthropometric studies of patients with 45,X have consistently described the typical body proportions and distinctive features associated with Turner syndrome. Reproductive capacity is almost universally absent in this subgroup, and although sporadic cases of spontaneous pregnancy have been reported, these remain exceptional.¹¹³

The most serious and life-threatening consequences of X-chromosome haploinsufficiency occur at the cardiovascular level, particularly during fetal development, when major congenital heart defects contribute to high mortality rates in fetuses with a 45,X constitution.^114–116 Structural cardiac anomalies are especially prevalent in cases of pure monosomy X,¹¹⁷ with coarctation of the aorta being the most frequently reported malformation, occurring in both preductal and postductal forms.¹¹⁸ Other cardiovascular malformations include bicuspid aortic valve, pulmonary venous anomalies, and hypoplastic left heart syndrome, which contribute substantially to morbidity and mortality in this subgroup.^119–121

In addition, hearing impairment and auricular malformations are strongly associated with the 45,X karyotype. Studies demonstrate that both sensorineural hearing loss and external ear anomalies occur at significantly higher rates in patients with monosomy compared with other subgroups,^122,123 findings consistent across multiple cohorts. Similarly, renal malformations are more frequently identified in individuals with 45,X, further underscoring the broader clinical severity of this karyotype.¹²⁴

Individuals with a 45,X karyotype exhibit a distinctive response pattern to recombinant growth hormone therapy. During the first year of GH treatment, girls with a 45,X karyotype demonstrate a robust growth response, with a marked increase in height velocity comparable to that observed in other karyotypic forms of Turner syndrome. Kasprzyk et al. reported that first-year improvements in height were not significantly different between individuals with homogeneous complete X monosomy and those with mosaicism or structural abnormalities, suggesting that 45,X patients initially respond well to GH therapy.¹²⁵

However, by the second year of treatment, this favorable response diminishes. Kasprzyk et al. observed that growth velocity in 45,X patients declined considerably compared with other karyotype groups. The reduction in second-year height velocity, measured as the change in height SDS, was significantly more pronounced in the 45,X group, whereas patients with mosaicism or marker chromosomes maintained a higher growth trajectory.^124,126 This finding indicates that the early benefit in homogeneous monosomy X is followed by a sharper deceleration of growth relative to mosaic karyotypes.

After three years of GH therapy, differences between karyotype groups become more evident. Girls with a 45,X karyotype achieve substantially smaller overall height gains than those with mosaic karyotypes. While mosaic patients demonstrate notable improvements in height SDS and approach their genetic target height, homogeneous monosomy X patients exhibit limited catch-up growth. This suggests that the long-term efficacy of GH therapy is reduced in patients with a pure 45,X karyotype.^127–129

Interestingly, the growth profiles of 45,X patients resemble those of individuals with isochromosome Xq. Both groups show attenuated responses to GH therapy, including a similar reduction in growth velocity during the second year and limited overall SDS gains after 3 years of treatment. These similarities reflect a shared biological mechanism: both 45,X monosomy and isochromosome Xq involve either complete loss of one X chromosome or absence of the short arm, leading to SHOX haploinsufficiency. This genetic deficit likely explains the poorer outcomes observed in these groups compared with patients with mosaicism, who retain partial SHOX gene function.^125,129,130

In contrast, Choi et al. found that although girls with a 45,X karyotype began GH treatment at a disadvantage, with lower baseline height SDS and slower early growth velocities compared with mosaic patients, long-term differences diminished over time. By the third year of therapy, improvements in height SDS were comparable across karyotype groups, suggesting that prolonged GH administration may compensate for the initial delay observed in 45,X patients.¹³¹ These findings challenge the assumption that 45,X monosomy is inherently associated with a poorer growth prognosis under GH therapy and emphasize the importance of treatment duration and follow-up in determining final height outcomes.¹³²

Mosaicism

Although the classic karyotype in Turner syndrome is 45,X, approximately 30–40% of patients present with mosaicism, characterized by the coexistence of a second cell line such as 45,X/46,XX; 45,X/47,XXX; 45,X/46,XY; or 45,X/47,XYY.¹⁰⁹

45,X/46,XX

The most frequent form of mosaicism is 45,X/46,XX, accounting for approximately 15% of cases. This karyotype combines a normal cell line with an abnormal cytogenetic complement.¹³³ Clinically, these patients may display a milder or even near-normal phenotype compared with classic TS. Spontaneous menstruation occurs in approximately 3% of females with pure 45,X monosomy but may be observed in up to 20% of mosaic individuals. Adult height is generally greater in mosaic patients, and the likelihood of somatic anomalies is lower compared with monosomy X.

Psychiatric comorbidities have also been reported. Notably, a higher proportion of patients with TS and schizophrenia exhibit a 45,X/46,XX mosaic pattern. It has been proposed that gene dosage effects may lead to abnormal expression of X-linked genes implicated in schizophrenia susceptibility.¹³⁴ The HOPA gene, located on Xq13, has been identified as a candidate gene associated not only with schizophrenia but also with intellectual disability and thyroid dysfunction.¹³⁵

45,X/46,XY

A 46,XY cell line is present in approximately 5–10% of patients with TS.¹³⁶ Clinical expression in this group is highly variable, ranging from a typical TS phenotype to normal male appearance, varying degrees of masculinization, male pseudohermaphroditism, or mixed gonadal dysgenesis, which carries malignant potential.³³ Importantly, phenotype does not reliably predict the presence of a Y chromosome cell line. Even individuals with a typical female phenotype and no signs of virilization may harbor Y chromosome material. Given the elevated risk of germ cell tumors, particularly gonadoblastoma, reported in approximately 15% of patients with 45,X/46,XY mosaicism, close clinical and oncologic follow-up is essential.¹³⁷

45,X/47,XXX

Triple X syndrome occurs in approximately 1 in 1000 live-born females. Clinical features may include tall stature with disproportionately large hands and feet, microcephaly, hypotonia, seizures, genitourinary malformations, and premature ovarian failure. Pubertal onset, sexual development, and fertility are often typical, although affected individuals may present with speech and motor delays, learning disabilities, attention deficits, and behavioral problems.¹³⁸

This karyotype is relatively rare in TS, accounting for approximately 3–4% of cases. It arises due to postzygotic nondisjunction within the disomic cell line.¹³⁹ These individuals typically exhibit a milder phenotype with fewer characteristic TS features, although ovarian dysfunction may still occur. Spontaneous menarche and fertility are more common vs monosomy X, with reported rates of 84% and 69%, respectively.¹⁴⁰ Neurocognitive development, including the risk of intellectual disability, does not differ significantly between patients with 45,X and those with 45,X/47,XXX or more complex mosaic karyotypes such as 45,X/46,XX/47,XXX. Importantly, the proportion of 45,X to 47,XXX cells identified in karyotype analysis has limited predictive value, as distributions vary considerably across tissues.^139,140

Kasprzyk et al. reported that karyotype significantly influences the growth response to GH therapy in Turner syndrome. In their 3-year prepubertal cohort, girls with mosaicism or marker chromosomes maintained higher growth velocities beyond the first year of treatment and achieved greater cumulative height gains by year 3 than those with pure 45,X monosomy or isochromosome Xq. This finding suggests that mosaic patients are more likely to sustain catch-up growth, whereas nonmosaic groups show an early benefit that diminishes more rapidly over time.¹²⁵

In contrast, other studies have not confirmed this sustained advantage. Park et al., in a smaller 3-year study, found no significant effect of karyotype on changes in height SDS, although the first year of GH therapy was associated with the greatest gains across all subgroups.¹³¹

Similarly, Choi et al., analyzing a larger multicenter cohort of 194 girls, reported that those with mosaicism without structural abnormalities exhibited higher first- and second-year growth velocities than patients with 45,X; however, by the third year, improvements in height SDS were comparable across groups. This suggests that the early growth advantage observed in mosaicism does not persist over the long term with continued GH therapy.¹³¹

A recent systematic review by Aversa et al. further supports this observation, concluding that karyotype is not a consistent predictor of adult height or overall growth response to GH therapy. Instead, outcomes are more strongly influenced by factors such as age at treatment initiation, GH dosing, and timing of pubertal induction.¹⁴¹

Structural abnormalities of the X chromosome

Isochromosome X [46,X,i(X)]

An isochromosome is a structural abnormality in which both arms of a chromosome are identical due to abnormal centromere division. The most frequent structural X-chromosome abnormality in TS is 46,X,i(Xq), with or without mosaicism.⁴ Short stature is particularly common in this group, likely due to SHOX haploinsufficiency.¹⁴² While 46,X,i(Xq) typically results in growth impairment, the rare 46,X,i(Xp) karyotype is more often associated with gonadal dysfunction. Autoimmune thyroid disease is also common, with prevalence increasing from the first to the third decade of life in patients with isochromosome karyotypes.¹⁴³ In addition, both 45,X and 46,X,i(Xq) patients show a higher risk of hearing loss compared with mosaic individuals, and hearing decline correlates with age.¹⁴⁴

Ring chromosome [46,X,r(X)]

Ring chromosomes arise from terminal breaks on both arms of the X chromosome, followed by fusion of the ends, often resulting in partial monosomy. Approximately 6% of patients with TS carry a ring X chromosome, usually in combination with a 45,X cell line. Clinical features include atypical TS signs such as short stature, ovarian dysgenesis, and lymphatic abnormalities; however, neurological and developmental disorders – including intellectual disability, autism spectrum disorder, and structural brain abnormalities – are more frequent in this group compared with 45,X.²⁷ Phenotypic variability depends on the presence or absence of the X-inactivation center. If the XIST locus at Xq13 is absent, the abnormal X chromosome cannot be inactivated, leading to functional disomy and more severe manifestations, including skeletal anomalies, pigmentation defects, or Kabuki-like features. Hyperinsulinemic hypoglycemia has also been reported, particularly in mosaic cases.^145–147

Deletions (Xp or Xq)

Xp deletions occur in approximately 2% of patients with Turner syndrome. Complete loss of the short arm results in short stature, gonadal dysgenesis, and typical TS stigmata, whereas partial deletions produce variable phenotypes. The terminal Xp22.33–Xp22.12 region contains the SHOX gene, which escapes X inactivation and is dosage dependent. SHOX haploinsufficiency leads to growth restriction and skeletal anomalies, including short metacarpals, cubitus valgus, high-arched palate, Madelung deformity, and mesomelic dysplasia.^148,149 SHOX mutations are identified in approximately 17% of cases of idiopathic short stature and in up to 90% of Leri-Weill syndrome cases.¹⁴⁵ Genes located on Xp and Yp also play a key role in cardiovascular development, with bicuspid aortic valve (30%), coarctation of the aorta (12%), and, less frequently, hypoplastic left heart syndrome (10%) reported in this population.^150,151

The impact of structural X-chromosome abnormalities on growth hormone responsiveness in Turner syndrome remains debated. Kasprzyk et al. reported that girls with 45,X monosomy and isochromosome Xq exhibited a robust first-year response to recombinant GH; however, growth velocity declined markedly by the second year, resulting in significantly smaller 3-year gains in height SDS compared with patients with mosaic or marker karyotypes. This finding suggests that structural karyotypes involving loss of Xp – and consequently SHOX haploinsufficiency – may be associated with an attenuated medium-term growth response.¹²⁵

In contrast, Choi et al. found no significant differences in 3-year height SDS gains between patients with structural abnormalities, including ring X, and those with 45,X or mosaic karyotypes. Although some year-to-year variability in growth velocity was observed – particularly a stronger second-year response in mosaic patients – the overall improvement in growth converged across karyotype groups after sustained GH therapy¹³¹ (Table 1).

Table 1.

Summary of comparative findings regarding growth hormone responsiveness across cytogenetic subtypes of Turner syndrome.

Karyotype	45,X	Mosaicism (45,X/46,XY)	Isochromosome Xq	Ring chromosome	Xp deletions
Clinical phenotype	Most severe TS phenotype; short stature; increased cardiac (BAV, coarctation) and renal anomalies; near-universal ovarian failure; SHOX haploinsufficiency	Milder phenotype; often taller than 45,X; fewer somatic anomalies; increased likelihood of spontaneous puberty and menstruation	Short stature due to SHOX haploinsufficiency (Xp loss); increased risk of autoimmune thyroid disease and hearing impairment; phenotype often resembles 45,X	TS features with variable neurodevelopmental involvement; height variable; phenotype depends on presence or absence of the X-inactivation center	SHOX haploinsufficiency leading to short stature and skeletal abnormalities (e.g., Madelung deformity); cardiac defects; ovarian failure in cases of extensive Xp loss
GH response – Kasprzyk et al. (year 1)	Strong first-year catch-up growth	Sustained growth beyond year 1	Initial growth followed by decline after year 1	Among the best 3-year gains; sustained growth after year 1	Early robust GH-induced catch-up growth
GH response – Kasprzyk et al. (year 2)	Marked slowdown during years 2–3	Continued growth; greatest overall gains compared with 45,X and i(Xq)	Reduced response compared with mosaicism	Continued steady growth trajectory	Possible decline when Xp/SHOX is absent
GH response – Kasprzyk et al. (year 3)	Smaller cumulative 3-year height gain than mosaicism	Greatest cumulative 3-year gains among all groups	Lower 3-year gain compared with mosaicism	Sustained favorable 3-year growth	With sustained therapy, height SDS may converge with other karyotypes
GH response – Choi et al. (year 1)	Lowest baseline height SDS at treatment initiation	Faster growth during years 1–2	ΔSDSΔ during years 1–3 similar to other groups	ΔSDS during years 1–3 similar to other groups	ΔSDS during years 1–3 similar to other groups
GH response – Choi et al. (year 2)	ΔSDS comparable to other groups by year 2	–	–	–	–
GH response – Choi et al. (year 3)	ΔSDS comparable to other groups by year 3	–	–	–	—
GH response – Park et al. (years 1–3)	No genotype-related differences in GH response after 3 years of treatment	No genotype-related differences in GH response after 3 years of treatment	No genotype-related differences in GH response after 3 years of treatment	No genotype-related differences in GH response after 3 years of treatment	No genotype-related differences in GH response after 3 years of treatment

GH, growth hormone; TS, Turner syndrome; BAV, bicuspid aortic valve; SHOX, short stature homeobox gene; ΔSDS, change in height standard deviation score over time.

Discussion

In this review, we observed that responsiveness to growth hormone treatment in Turner syndrome varies according to karyotypic subtype. Girls with 45,X monosomy demonstrate an initially robust growth acceleration with GH, consistent with the well-documented first-year “catch-up” phenomenon in TS; however, their response attenuates more markedly in subsequent years. By contrast, patients with mosaic karyotypes or those harboring structural abnormalities of the X chromosome (eg, isochromosome Xq or ring X) tend to maintain higher growth velocity over time. During the second and third years of therapy, the 45,X group exhibits a sharper decline in height velocity compared with mosaic patients, who continue to grow at a relatively steady pace. Consequently, over the multiyear course of treatment, patients with 45,X monosomy show smaller cumulative height gains relative to baseline and target heights, whereas mosaic and certain structurally abnormal karyotype groups achieve more sustained improvements. This pattern – an early growth spurt in 45,X followed by declining efficacy – is consistent with findings by Kasprzyk et al., who reported that girls with 45,X initially respond well to GH but subsequently exhibit reduced height velocity compared with those with mosaic karyotypes.¹²⁶ These observations suggest that although GH therapy can partially overcome intrinsic growth deficits in monosomy X, its long-term effectiveness may be more limited in this subgroup compared with other karyotypes.¹⁵²

Several other studies, however, have reported minimal or no differences in GH-mediated growth outcomes across TS karyotypes. Park et al. followed GH-treated girls with TS for 3 years and found no statistically significant difference in height gain between those with 45,X and those with mosaic or structural abnormalities.¹³² Similarly, a large cohort analysis by Choi et al. demonstrated that although baseline height and early growth velocities differed by karyotype, the overall increase in height SDS after 3 years of GH therapy was comparable across groups.¹³¹ These contrasting findings highlight an ongoing debate in the literature. While some studies suggest that cytogenetic subtype influences the trajectory of GH response, others indicate that karyotype does not significantly affect final height outcomes. This inconsistency underscores the need for caution when interpreting individual studies and highlights the importance of further research to clarify whether genotype meaningfully modifies treatment response in TS.

Several factors may explain these discrepancies. Sample size and statistical power are critical considerations, as subdivision by karyotype often results in relatively small groups. Studies with limited numbers of 45,X or mosaic patients may lack the power to detect modest differences, potentially leading to conclusions of “no difference.” Patient selection and baseline characteristics also play a key role. Age at GH initiation and baseline height deficit vary across cohorts and may confound comparisons. For example, if 45,X patients initiate treatment later than mosaic patients, differences in outcomes may reflect treatment timing rather than karyotype. Indeed, earlier initiation of GH therapy is a well-established predictor of improved height outcomes in TS.¹⁵³ Variability in GH dosing and treatment duration further complicates comparisons. Higher GH doses or adjunctive therapies, such as low-dose estrogen or anabolic agents, may enhance growth across all karyotypes and obscure intrinsic differences. Conversely, studies using lower doses or shorter treatment durations may better reveal underlying variability in response.¹⁵⁴ Additionally, outcome measures are not uniform across studies. Some focus on short-term changes in height velocity, whereas others evaluate final adult height. Karyotype may influence growth dynamics without substantially affecting final height, which may explain discrepancies between studies examining intermediate versus long-term outcomes.¹⁵⁵ Finally, growth in Turner syndrome is influenced by multiple factors, including nutrition, comorbid conditions, and genetic polymorphisms affecting GH action.¹⁵⁶ These variables vary across populations and further complicate the isolation of karyotype-specific effects. Taken together, these considerations suggest that inconsistencies in the literature likely reflect methodological differences and population heterogeneity rather than true biological contradictions.

Conclusions

The available evidence regarding whether cytogenetic subtypes of Turner syndrome influence the response to growth hormone therapy remains inconclusive. Some studies report differences between karyotypes, whereas others do not, likely reflecting variability in study design, sample size, and treatment protocols. At present, definitive conclusions cannot be drawn, and further well-designed, large-scale studies are required to clarify the potential role of karyotype in modulating growth response.

Authors’ contributions

Study design: Ingrid-Ioana Herșcovici, Monica Cristina Pânzaru, Cristina Rusu. Data collection: Not applicable. Statistical analysis: Not applicable. Data interpretation: Not applicable. Manuscript preparation: Ingrid-Ioana Herșcovici, Cristina Preda, Maria-Christina Ungureanu, Letiția Leuștean. Literature search: Ingrid-Ioana Herșcovici, Georgiana Constantinescu. Funding: Not applicable.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the authors did not use AI-assisted technologies.

Funding

The authors report no funding.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

No financial support was received for this study.