Growth Hormone Insensitivity and Primary IGF-1 Deficiency (Laron Syndrome and Related Disorders)

Class of disorders of the growth hormone–IGF-1 axis in which growth hormone is produced in normal or increased amounts but fails to generate, transport, release or act through IGF-1: Laron syndrome (GHR), partial and dominant-negative insensitivity (GHR), recessive and dominant-negative STAT5B deficiency, acid-labile subunit deficiency (IGFALS), IGF-1 deficiency (IGF1), Dauber-Argente type short stature (PAPPA2) and IGF-1 resistance (IGF1R).

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From Laron's description to the growth hormone receptor

In 1966, Zvi Laron, Athalia Pertzelan and S. Mannheimer published in the Israel Journal of Medical Sciences the description of a "genetic pituitary dwarfism with high serum concentration of growth hormone", which they already questioned as a new inborn error of metabolism [37]. The children described belonged to consanguineous Jewish families of Yemenite origin and had the clinical appearance of hypopituitarism with high immunoreactive GH; reviews differ on the number of siblings in the initial report, two in one and three in others [2, 7, 17]. In Israel, the first 20 cases (13 female and 7 male) occurred in Oriental Jews, and non-Jewish cases of Dutch and Arab origin followed [4]. The hypothesis of an abnormal GH molecule was abandoned when it was shown that these patients' GH reacted normally with antisera and bound normally to receptors, that there was no generation of somatomedin (IGF-1) and that the patients' liver membranes did not bind iodine-125-labelled GH [2, 4].

Molecular proof came in 1989. Godowski and colleagues characterised the structure of the GHR gene (nine coding exons spread over at least 87 kb of chromosome 5) and found, in two of nine patients with Laron dwarfism, a deletion of a large part of the extracellular domain spanning non-consecutive exons [38]. In the same year, Amselem and colleagues demonstrated by genetic linkage, in two consanguineous Mediterranean families, cosegregation of the disease with intragenic GHR markers and identified the Phe96Ser substitution (mature protein numbering; NM_000163.5:c.341T>C, p.(Phe114Ser)) in the extracellular domain, absent in seven other patients of different origins, which showed allelic heterogeneity from the outset [39, 40].

1.2. Expansion of the class

Over the following decades, the category expanded in two directions. The first was the discovery of defects downstream of the receptor: deletion of IGF1 (Woods, 1996), variants in IGF1R (Abuzzahab, 2003), STAT5B (Kofoed, 2003), IGFALS (Domené, 2004) and PAPPA2 (Dauber, 2016) [41–45]. The second was the recognition of mild, so-called non-classical forms: heterozygous dominant-negative variants of GHR (Ayling, 1997) and STAT5B (Klammt, 2018), the GHR intronic pseudoexon 6Ψ (Metherell, 2001) and the dosage effect in heterozygotes for IGFALS, IGF1 and GHR [2, 4, 46, 47]. A classification of IGF deficiencies proposed in 1996, when some of the categories were still theoretical, was gradually filled by real patients [17].

1.3. Nomenclature and operational definitions

GHI is defined as the inability of normal GH concentrations to produce the usual response, with low IGF-1, normal or raised GH and failure of IGF-1 to rise after exogenous GH; IGF-1 deficiency is the common biochemical feature [7]. Storr and colleagues define it as the disruption of all or some of the physiological mechanisms of GH action, of genetic or acquired cause, with degrees ranging from almost total absence of peripheral response to subtle abnormalities [2]. The regulatory designation "severe primary IGF-1 deficiency" (SPIGFD) is not a genetic diagnosis: in the United States (USA) it corresponds to height ≤ −3.0 SD, basal IGF-1 ≤ −3.0 SD and normal or raised GH; in the European Union (EU), to height ≤ −3.0 SD, basal IGF-1 below the 2.5th percentile for age and sex, GH sufficiency and exclusion of secondary forms [32, 33]. The term includes patients with variants in GHR, in post-receptor signalling and in IGF1, and also patients without an identified molecular cause [32, 48].

The class comprises (1) disorders with IGF-1 deficiency due to GH insensitivity or failure of synthesis (GHR, STAT5B, IGF1), (2) disorders of the bioavailability of circulating IGF-1 (IGFALS, PAPPA2) and (3) IGF-1 resistance (IGF1R), which is the mirror image of the deficiency, with normal or high IGF-1 [2, 17]. Storr's classification adds to these categories the effect of activated SHP-2 (PTPN11, Noonan syndrome), IGF2 variants and neutralising anti-GH antibodies in GH1 deletion, and separates acquired causes: malnutrition, parenchymal liver disease, poorly controlled type 1 diabetes and chronic inflammatory diseases, such as juvenile idiopathic arthritis, Crohn's disease, coeliac disease and anorexia nervosa [2]. Noonan syndrome, Silver-Russell syndrome, 3M syndrome and isolated GH deficiency belong to the differential diagnosis (section 6).

2. Molecular Genetics and Pathophysiology

2.1. The GH–IGF-1 axis in growth

Early embryonic growth depends mainly on IGF-1 and IGF-2, fetal and early neonatal growth on IGF-1, and childhood growth on GH and IGF-1; this sequence explains why the distinction between growth failure of prenatal and postnatal onset is one of the most useful clinical tools [49]. GH-regulated IGF-1 production is a postnatal phenomenon; in utero, IGF-1 depends mainly on nutrition and insulin [2, 7]. In mice, inactivation of Igf1 or Igf2 reduces fetal growth by about 40% [2, 7]. The old somatomedin hypothesis, according to which GH would act only through circulating hepatic IGF-1, gave way to the dual effector hypothesis: GH also regulates local IGF-1 production, with autocrine and paracrine action, and directly stimulates the differentiation of growth plate prechondrocytes, while IGF-1 stimulates their clonal expansion [2, 7].

GH circulates free or bound to GHBP, which is the extracellular domain of the receptor released by proteolysis and accounts for about half of total GH [7]. On binding to GHR, GH activates the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5B (STAT5B) pathway and, in the liver, transcription of IGF1, IGFBP3 and IGFALS, as well as of the negative regulators of the suppressor of cytokine signalling (SOCS) family [2]. Secreted IGF-1 circulates bound to six binding proteins (IGFBPs), mainly IGFBP-3 and IGFBP-5; about 80–85% of these binary complexes associate with ALS in a 1:1:1 ternary complex that prolongs the half-life of IGF-1 and retains it in the circulation [17, 32]. IGFBPs have higher affinity for IGF-1 (dissociation constant of about 10⁻¹⁰ M) than the IGF1R receptor itself (10⁻⁸ to 10⁻⁹ M), and release of IGF-1 depends partly on cleavage of IGFBP-3 and IGFBP-5 by the metalloproteinase PAPP-A2 [2, 17]. Free IGF-1 acts on IGF1R, a receptor tyrosine kinase that activates the phosphatidylinositol 3-kinase (PI3K)–AKT and RAS–mitogen-activated protein kinase (MAPK) pathways [17, 30]. Each gene of the class interrupts one of these steps, and the pattern of IGF-1, IGFBP-3, ALS and GHBP indicates the level of the defect (table 2.1).

Table 2.1. Level of the defect and typical biochemical profile [2, 7, 17]

N: normal; ↑: increased; ↓: decreased; —: not described in the sources. The review by Mastromauro attributes low IGF-1 to IGF-1 resistance, in contradiction with the series of IGF1R patients, in whom IGF-1 is above the mean for age [7, 17, 30].

2.2. GHR and Laron syndrome

GHR (5p13.1-p12) spans about 298 kb and has 10 exons; exons 2 to 10 encode a 638-amino-acid prepeptide whose 18-residue signal peptide is removed, leaving a 620-amino-acid mature protein with an extracellular GH-binding domain (exons 2–7; 246 residues), a transmembrane domain (exon 8; 24 residues) and an intracellular domain (exons 9 and 10; 350 residues) [2, 7]. There is a common isoform lacking exon 3 [2], and the exon 3 deletion polymorphism is associated with an increased response to GH [8]. GHR is a type I cytokine receptor without intrinsic kinase activity, present at the membrane as a preformed homodimer; each monomer recruits a JAK2 through intracellular boxes 1 and 2, binding of one GH molecule reorients the subunits, the JAK2 molecules transphosphorylate and phosphorylate the seven intracellular tyrosines, three of which serve as redundant docking sites for STAT5B [2, 7, 17]. The difference between mature protein numbering (used in the historical literature) and the prepeptide numbering used by Human Genome Variation Society (HGVS) nomenclature is 18 residues, which explains designations such as "E180" or "R43X" [2, 50].

GHR variants are the most frequent cause of primary GHI [7]. More than 70 homozygous or compound heterozygous variants have been described in more than 250 patients, or about 100 variants in more than 300 patients according to a more recent series; in a compilation of 93 variants, 68 were located in the extracellular domain, 13 in introns, 10 in the intracellular domain and 2 in the transmembrane domain [2, 7, 51]. The types include deletions, RNA processing defects, nonsense and missense, and the genotype-phenotype correlation is weak: in a series of 82 patients from 23 countries, 15 variants in 27 patients showed no relationship between variant type or exon and severity, and the patients' height did not correlate with parental height [4, 7]. Variants that prevent GH binding reduce circulating GHBP, which was undetectable or low in 63 of those 82 patients; the 19 with detectable GHBP had less affected mean height (−4.9 versus −6.5 SD) [4, 7].

Some variants preserve GH binding and alter receptor dimerisation or trafficking. The Ecuadorian founder variant "E180splice", in mature numbering, corresponds to NM_000163.5:c.594A>G, p.(Glu198=), NC_000005.10:g.42699978A>G: it is synonymous at the protein level, but creates a cryptic splice donor site in exon 6, removes 8 amino acids from the extracellular domain and gives rise to a receptor that is probably misfolded and degraded [2, 40, 50, 52]. The "R43X" variant, recurrent at a CpG dinucleotide, is NM_000163.5:c.181C>T, p.(Arg61Ter) [4, 40, 50]. Both are classified as pathogenic in ClinVar, with several submitters and no conflict [40].

2.3. Non-classical forms of GHR

Heterozygous dominant-negative variants are located in the intracellular domain. In the first case (Ayling, 1997), a variant of the intron 8 acceptor site (−1 G>C) caused skipping of exon 9, loss of the proline-rich JAK2-binding motif and a truncated receptor with only 7 cytoplasmic amino acids that heterodimerises with the normal receptor, accumulates at the surface and blocks STAT5 activation [4]. Only seven patients with proven heterozygous GHR variants and a relevant phenotype have been described, including four variants from Vairamani: NM_000163.5:c.964dup p.(Val322Glyfs9), c.945+2T>C (splice donor site), c.899dup p.(Val301Serfs7) and c.920_921ins14 (published designation, without the inserted sequence specified) [2, 50]. GHBP is high-normal or very high, because the mutant extracellular domain continues to be expressed [2]. A 2024 review of monogenic causes of familial short stature includes heterozygous GHR variants, dominant-negative STAT5B, IGFALS and IGF1R among the causes with vertical transmission [53].

The 6Ψ pseudoexon, NM_000163.5:c.618+792A>G (g.42700794A>G), described in 2001 in four siblings of a consanguineous Pakistani family, activates a donor site in intron 6 and inserts 108 nucleotides between exons 6 and 7, that is, 36 amino acids in a region of the extracellular domain involved in homodimerisation [2, 47, 50]. Aberrant splicing is incomplete and normal and mutant transcripts coexist in variable proportions, which explains the phenotypic variability within the same family [2, 51]. In 2021 the 6Ω pseudoexon was described, NM_000163.5:c.618+836T>G (g.42700838T>G in GRCh38; g.5:42700940T>G in GRCh37), 44 bp downstream of 6Ψ, which creates an AGGT donor site, includes 151 bp with a frameshift and produces a truncated receptor lacking the transmembrane and intracellular domains, which accumulates in the extracellular medium and does not activate STAT5B; unlike 6Ψ, it causes severe GHI and was the first deep intronic variant associated with severe postnatal growth failure [50, 51]. These variants are not detected by panels restricted to coding regions and flanking intronic sequences.

2.4. STAT5B

STAT5B is a latent cytoplasmic transcription factor, phosphorylated on tyrosine 699 by JAK2 downstream of GH, prolactin, interleukin-2 and other cytokines; it dimerises, enters the nucleus and binds interferon-gamma-activated sequence (GAS) elements, being the main transducer from GHR to the IGF1 gene and a regulator of regulatory T-cell homeostasis; STAT5B deficiency is listed among the combined immunodeficiencies with a locus at 17q21.2 [2, 54, 55]. Of the seven human STATs, four (STAT1, 3, 5A and 5B) are activated by GHR, but only STAT5B deficiency is consistently associated with severe growth failure; STAT5A, with more than 90% amino acid identity, does not compensate in humans, unlike in the Stat5b−/− mouse [2, 17].

In the recessive form (GHISID1), the seven homozygous inactivating variants compiled by Storr include one nonsense and four frameshift variants, all with premature termination, and two missense variants in the SH2 domain: p.Ala630Pro, which is unstable, and p.Phe646Ser, without transcriptional activity; none affects the transactivation domain [2]. The first variant, described in a 16.5-year-old Argentinian girl, is NM_012448.4:c.1888G>C, p.(Ala630Pro) [12, 40, 43]. The p.Trp631* variant treated by Muthuvel corresponds to NM_012448.4:c.1892G>A, p.(Trp631Ter) [40, 56]. In the dominant-negative form (GHISID2), three private missense variants described in three families are phosphorylated and dimerise with the normal protein, but p.Gln177Pro (coiled-coil domain; c.530A>C) does not enter the nucleus, and p.Gln474Arg and p.Ala478Val (DNA-binding domain; p.Ala478Val is c.1433C>T) do not bind the response elements [40, 46]. The ClinVar classification of p.Ala478Val as a variant of uncertain significance (VUS), by a single submitter, diverges from the published functional and segregation evidence [40, 46]. In 164 children with GHI without a GHR cause studied by the same groups, only three families had a dominant-negative variant [46]. Heterozygous carriers of recessive variants have low-normal height and no immune disease, which indicates that one normal allele is sufficient [2]. Somatic activating STAT5B variants (for example p.Asn642His) in T-cell and natural killer (NK) cell neoplasms and the STAT5B-RARA fusion of acute promyelocytic leukaemia are acquired events, without germline significance [2, 54].

2.5. IGF1

The IGF1 gene spans more than 84 kb at 12q23.2, with six exons and two promoters; exons 3 and 4 encode the B, C, A and D domains of the 70-amino-acid mature peptide [17, 32]. The first human variant (Woods, 1996) was a homozygous deletion of exons 4 and 5 (p.Asn74Argfs*9), with undetectable serum IGF-1 [17, 41]. Four homozygous missense variants in the C or A domains followed; three mutant peptides were detectable in serum with reduced affinity for IGF1R, and p.Arg98Trp, identified in siblings from a primordial dwarfism cohort, has not been studied functionally and is a VUS [17]. The mildest case, described as p.R36Q in mature peptide numbering in one review and as p.Arg84Gln in another, reduces affinity for IGF1R two- to threefold [2, 17]. ClinVar contains truncating variants classified as pathogenic by a single submitter, such as NM_000618.5:c.327C>A, p.(Cys109Ter), and c.228del, p.(Thr77fs) [40].

Inheritance is recessive for the full phenotype, but heterozygosity has a dosage effect: nine heterozygotes from one family had smaller head circumference (−1.0 versus 0.5 SD), birth weight (3048 versus 3358 g) and height (−1.0 versus −0.4 SD) than non-carriers; in the family with NM_000618.5:c.243_246dup p.(Ser83Glnfs*13) [50], the children had −4.1 and −4.6 SD and the adult carriers −3.4 versus −1.6 SD in non-carriers; it has been proposed that haploinsufficiency of maternal origin costs about 2 SD and of paternal origin 1 SD, through placental dysfunction [2]. The 262 kb deletion that includes the whole gene (boy aged 8 years and 5 months, head circumference −3.4 and height −2.7 SD, low-normal IGF-1, inherited from his short father) and the variants NM_000618.5:c.402+1G>C and c.402+1G>A (exclusion of exon 4) [50] confirm pathogenic haploinsufficiency [2, 17]. GenCC records divergent classifications of the mode of inheritance: AR (strong or definitive), semidominant (strong) and AD (limited) [21].

2.6. IGFALS

IGFALS (16p13.3) spans 3.3 kb and has two exons; exon 1 encodes only 5 of the 605 amino acids and all variants described are located in exon 2 [17]. ALS is a glycoprotein of about 85 kDa of the leucine-rich repeat family, with 21 motifs arranged in a horseshoe, synthesised in hepatocytes under GH control [17, 57]. In its absence the ternary complex does not form and IGF-1 and IGFBP-3 are cleared rapidly; local IGF-1 production in the growth plate is maintained or increases with GH hypersecretion, which attenuates the growth failure [2, 17]. The first homozygous variant was NM_004970.3:c.103del p.(Glu35Lysfs87) (2004; published as c.103delG), in a boy whose height (−2.1 SD) contrasted with the extreme deficiency of IGF-1, IGFBP-3 and ALS [17, 44]. More than 30 homozygous or compound heterozygous variants have been described in more than 62 patients: missense, nonsense, duplications, insertions and deletions [17]. In Scaglia's Latin American series there were, in the published protein designations (NP_004961.1), p.Glu35Glyfs17, p.Glu35Lysfs*87 (= NM_004970.3:c.103del), p.Leu213Phe, p.Asn276Ser, p.Leu409Phe, p.Ala475Val and p.Ser490Trp, and seven of eight patients did not form ternary complexes in vitro [58]. The p.D440N variant (published designation, = p.Asp440Asn) creates a new N-glycosylation site, with hyperglycosylated ALS and altered secretion and complex formation [17]. Heterozygotes lose about 1.0 SD in height relative to non-carriers, and homozygotes a further 1.0–1.5 SD, which led to the proposed designation "partial ALS deficiency" [2, 17].

2.7. PAPPA2

PAPPA2 (1q25.2) encodes a metalloproteinase of the pappalysin family with 1791 amino acids and more than 200 kDa, which specifically cleaves IGFBP-3 and IGFBP-5 and releases IGF-1 from the ternary complex; it is highly expressed in the placenta and increases exponentially in pregnancy [2, 17]. In 2016 two families were described: one of Spanish ancestry with the homozygous insertion c.1927_1928insAT (described as p.D643fs25*; no ClinVar entry), with no detectable protein and absent from more than 60,000 exomes (including at least 700 Spanish individuals), and another of Palestinian ancestry with NM_020318.3:c.3098C>T, p.(Ala1033Val), expressed but without proteolytic activity [23, 40, 45]. The defect retains IGF-1 in the ternary complex: total IGF-1, IGFBP-3, IGFBP-5, ALS and IGF-2 are raised, but free, bioactive IGF-1 is low [45]. Mice with Pappa2 inactivation and with the human p.Ala1033Val variant reproduce the phenotype and showed that it is free IGF-1, not total IGF-1, that exerts feedback on GH secretion [17]. Common variants near PAPPA2 are associated with adult height in genome-wide association studies [2].

2.8. IGF1R

IGF1R (15q26.3) has 21 exons over 315 kb; the precursor has a 30-amino-acid signal peptide, is cleaved into α and β chains and forms an α2β2 tetramer, with affinity IGF-1 ≥ IGF-2 >> insulin [17]. The 15q26-qter deletions (MIM 612626) with microcephaly, severe IUGR and postnatal deficit suggested in 1991 the role of receptor haploinsufficiency; visible 15q deletions that include IGF1R may give a phenotype similar to Silver-Russell, and duplication or triplication of 15q encompassing it is associated with overgrowth [17, 59, 60]. The first point variants (Abuzzahab, 2003) were described in mature numbering as "Arg59stop", "Arg108Gln" and "Lys115Asn", which correspond to NM_000875.5:c.265C>T, p.(Arg89Ter), c.413G>A, p.(Arg138Gln), and c.435A>C, p.(Lys145Asn) [40, 42]. In ClinVar, these three historical entries appear with the classification "protective", without assertion criteria, an annotation that does not correspond to a clinical classification [40].

The dosage effect is clear: haploinsufficiency reduces growth and three copies are associated with tall stature [17]. Between 2016 and 2020 more than 40 variants were added to the roughly 20 already known; about 65% are missense and require functional proof, and 35% are nonsense, frameshift or splicing variants [17]. The four homozygotes described have variants in the α chain with residual function, which suggests that total absence of the receptor is lethal, as in the Igf1r−/− mouse, which dies in the perinatal period from respiratory failure [17]. ClinGen assigns IGF1R a haploinsufficiency score of 3, with no evidence of triplosensitivity [30]. Because deletion of the whole gene is an established mechanism, sequencing alone is not sufficient [30].

2.9. Other genes and mechanisms of the extended class

SHP-2, encoded by PTPN11, dephosphorylates STAT5B; the activating variants of Noonan syndrome reduce IGF-1 and the response to GH [2, 3]. Gain-of-function STAT3 variants reduce the transcriptional activity of STAT5B, but the growth failure appears to be mainly secondary to inflammation and immunosuppressants [2, 7]. IKBKB variants and PRKCA overexpression (alteration of the NF-κB pathway), as well as IκBα variants, have been associated with reduced GH sensitivity with short stature and immunodeficiency [2, 3]. Paternally expressed IGF2 variants cause a Silver-Russell phenotype with normal or high IGF-1 [17].

2.10. Penetrance, expressivity and modifiers

Laron syndrome has complete penetrance in homozygotes and compound heterozygotes, with wide variability of expression [4, 7]. In the Ecuadorian cohort, 58 heterozygous carriers of E180splice were not significantly shorter than 37 non-carrier relatives (−1.85 ± 1.04 versus −1.55 ± 0.96 SD), and had no reduction in GHBP, IGF-1, IGF-2, IGFBP-2 or IGFBP-3; a larger analysis suggested a mean reduction of about 0.55 SD [2, 5]. In 6Ψ patients, severity does not correlate with IGF-1, which suggests modifiers downstream of the receptor or environmental factors [2]. Variability within families with the same GHR, STAT5B or IGFALS variant and the possibility of digenic or oligogenic inheritance are recognised as gaps in the genotype-phenotype correlation [2, 17].

3. Clinical Spectrum and Manifestations by System

3.1. Laron syndrome: natural history

The classic phenotype results from IGF-1 deficiency from birth without response to endogenous GH. Birth weight and length are normal and growth failure becomes evident in the first year; the height deficit correlates with serum IGF-1, bone age is delayed and hands and feet are small [2, 3]. Height is usually below −4 SD and final height between −5 and −10 SD; in the international series of 82 patients from 23 countries the mean was −6.09 SD (range −2.2 to −10.4) and IGFBP-3 −7.99 SD [2, 4, 7]. In the untreated series summarised by the PES guideline, height lies between −4 and −10 SD in childhood and remains so in adulthood, with adult heights of 106–142 cm in men and 95–136 cm in women [31]. In the province of Loja, Ecuador, 20 patients aged 2 to 49 years had heights between −6.7 and −10.0 SD relative to American references [4].

The face is characteristic, owing to deficient growth of the endochondral sphenoid: prominent forehead, hypoplastic nasal bridge with shallow orbits, reduced facial height and a head that appears large because head circumference is much less affected than height; facial height correlates with stature [2, 3]. Computerised facial morphometry of 49 Ecuadorian patients quantified this reduction in vertical facial growth relative to 70 relatives and 14 people who were short for other reasons [4]. Other features are the "setting sun sign" (sclera visible above the iris at rest) in 25% of children under 10 years, blue sclerae, sparse hair before 7 years with frontotemporal recession, prolonged retention of the primary dentition with crowding of the permanent teeth, unilateral ptosis and facial asymmetry [3, 4].

In the musculoskeletal system there is reduced muscle mass with late walking, a high-pitched voice, thin skin with an aged appearance and limited elbow extension after 5 years [3]. In the Ecuadorian series, 15 of 20 patients had limited elbow extension, all had blue sclerae, 80% had acrohypoplasia (hand or foot below the 10th percentile for height), adults had relatively short limbs and all four women over 30 years had hip degeneration; in another series, avascular necrosis of the femoral head affected 25% [3, 4].

Metabolism is marked by hypoglycaemia, more frequent in infants and often asymptomatic, and by adiposity: body mass index (BMI) is low or normal in childhood and high in adults, the lean mass/fat mass ratio is markedly reduced, fat accumulates on the trunk and arms and leptin is raised [2, 3, 7, 61]. In the European registry, 19% of children with Laron had spontaneous hypoglycaemia before treatment, versus 2.6% of the other forms of SPIGFD [48]. Total cholesterol and low-density lipoprotein (LDL) cholesterol are raised, sweating is reduced and insulin resistance has been described in some series, although the Ecuadorian cohort has low insulin and homeostatic model assessment of insulin resistance (HOMA-IR) (see 3.8) [3, 52]. In the reproductive system, boys have micropenis or small genitalia in childhood, puberty is delayed (late menarche in 5 of 12 Ecuadorian women over 16 years) and fertility is preserved [3, 4, 61].

Cognition is heterogeneous. Ecuadorian patients have normal or above-average intelligence and, in 52 probands, above-average school performance, with no relationship between genotype and intelligence, whereas the Israeli series described reduced cognitive and motor function, possibly related to repeated hypoglycaemia [3–5]. A large Israeli cohort documented difficulties with school, mobility, clothing and adapting the environment in adulthood [3].

3.2. Non-classical forms of GHR

The seven published patients with dominant-negative variants had progressive growth failure, normal or high GH and low IGF-1, without craniofacial dysmorphism; heights ranged from −2 to −4.3 SD (mother and daughter with −3.6 SD in Ayling's family; −2 to −3.5 SD in a Japanese family; a Spanish girl with −4.3 SD and three affected generations) [2]. Of the 20 patients homozygous for the 6Ψ pseudoexon, 50% had Laron facial features, 95% came from consanguineous families and 90% were of Pakistani origin; height ranged from −1.7 to −5.9 SD (mean −4.1 ± 0.95) and IGF-1 from −1.0 to −6.8 SD, with no correlation between the two [2, 62]. The 6Ω pseudoexon, by contrast, gave severe phenotypes, with heights of −6.9 to −9.3 SD (see section 10) [51].

3.3. STAT5B deficiency

In the recessive form, size at birth is appropriate (8 of 9), although 6 of 9 were born before 37 weeks; postnatal growth failure is indistinguishable from that of Laron, with height of −3.0 to −9.9 SD in the first description (n=11), delayed bone age (7/7) and delayed puberty (7/8) [17]. Some patients have mild facial features, such as a prominent forehead, depressed nasal bridge and high-pitched voice [2, 17]. Serum prolactin is markedly raised in 6 of 8, a feature unique to this form, without macroprolactin or a pituitary tumour [2, 17]. The first patient measured −7.5 SD at 16.5 years and had T lymphopenia [2, 46].

Immune disease distinguishes this form from Laron. In 8 of 10 patients there was severe eczema and chronic lung disease from the first year, with fibrosis and lymphoid interstitial pneumonia; recurrent lung infections, chronic diarrhoea, herpetic keratitis, herpes zoster, severe and haemorrhagic varicella, juvenile idiopathic arthritis, thyroiditis, autoimmune cytopenias and coeliac-like enteropathy have been described [2, 7, 54]. The patient with p.Ala630Pro died of respiratory failure at 30 years; another patient underwent lung transplantation at 17.5 years and died at 22 years, as did his affected brother [2, 17]. A 16.4-year-old Turkish girl also had a bleeding diathesis due to defective platelet aggregation [12]. Two patients did not have severe lung disease, one of them surviving to 31 years [17]. Brain development and cognition are normal [7].

In the dominant-negative form, 11 patients from 3 families had heights down to −5.3 SD (probands with −5.3, −2.9 and −4.5 SD), delayed bone age and puberty and low IGF-1; IgE was raised in 8 of 9 carriers and most had mild eczema, one had bronchial asthma and another coeliac disease and autoimmune thyroiditis; lymphocyte subsets were normal and hyperprolactinaemia rare [2, 11, 46]. Three of four siblings in one family had microcephaly (−3 to −3.7 SD), and the affected parents had a milder phenotype (height about −1.5 SD, borderline IGF-1) [11]. The mean height of these patients is similar to that of carriers of dominant-negative GHR variants [2].

3.4. IGF-1 deficiency

Homozygotes have IUGR, microcephaly, intellectual disability and severe postnatal growth failure, a combination that overlaps with that of microcephalic primordial dwarfism [7, 17]. In the three most severe probands, head circumference was −8.0 to −4.9 SD and height −9.0 to −6.2 SD, with facial dysmorphism, sensorineural deafness and global delay; the first patient had insulin resistance [2, 17]. The patient with the mildest variant had head circumference −2.5 SD, height −4.5 SD and normal hearing [17]. Heterozygotes have a moderate deficit in height and head circumference (section 2.5) [2]. A Brazilian reference work includes IGF1 mutation or deletion in the differential diagnosis of Silver-Russell syndrome, because of short stature, triangular face, micrognathia, clinodactyly and pectus excavatum, with cognitive impairment in some cases [63].

3.5. Acid-labile subunit deficiency

The presentation is mild to moderate short stature (−2 to −3 SD before and during puberty; −4.0 to −2.0 SD in the published series; mean −2.31 ± 0.87 SD in 21 patients), without Laron craniofacial features, with pubertal delay mainly in boys and insulin resistance with hyperinsulinaemia and low IGFBP-1 [2, 14, 17]. The contrast between the extreme biochemical deficiency and the modest growth failure is the most characteristic feature [2]. The first patient was assessed at 14 years with a height of 145.2 cm (−2.05 SD), Tanner stage 1, 3 mL testes and a bone age of 12.5 years [14]. Some have a normal pubertal growth spurt and adult height, reduced bone mineral density and, in a series of five Turkish families, birth weight below −2 SD and reduced head circumference in homozygotes [2, 7]. Male fertility is preserved and father-to-son transmission has been documented [58].

3.6. Dauber-Argente type short stature (PAPPA2)

The five children of the two initial families had progressive postnatal growth failure, with heights of −1.0 to −3.8 SD and well below target height, moderate microcephaly, a small chin, long fingers, thin long bones (mainly fibulae, tibiae and femora), reduced lumbar mineral density (Z of −2.49 and −2.0 SD), reduced enamel and dentine density and mild fasting hyperinsulinaemia, without cognitive deficit or hearing loss [22, 45]. Bone age was equal to chronological age [45]. The oldest Palestinian patient had no pubertal growth spurt and reached a final height of −3.8 SD [22].

3.7. IGF-1 resistance

The constant triad is IUGR, postnatal growth without catch-up and microcephaly, with IGF-1 above the mean for age; haploinsufficient individuals usually have height of −2.5 to −3 SD and delayed bone age, and may have mild learning difficulties [30, 64]. Homozygotes and compound heterozygotes are more severe: IUGR, microcephaly, height of −3.75 to −5.9 SD, global delay, intellectual disability, insulin resistance in adolescence and sensorineural hearing loss [17]. About 10% of infants with IUGR remain small, and it was in this group and in short children with raised IGF-1 that the first variants were found [42]. In adult carriers, a survey showed no more comorbidities than in adults born small for gestational age (SGA) [35].

3.8. Cancer, diabetes, cardiovascular risk and longevity in Laron

In the Ecuadorian cohort followed since 1988 (99 patients with GHRD, 22 years of monitoring, plus 53 who died before 1988 and 1606 unaffected relatives), cancer was not a cause of death in any patient, versus 20% of deaths in relatives, and there was a single non-lethal tumour (papillary serous ovarian tumour); type 2 diabetes was absent (0/90; 95% confidence interval 0–4%), versus 5% of deaths and 6% of diseases in relatives [52]. Insulin (1.4 versus 4.4 µU/mL) and HOMA-IR (0.34 versus 0.96) were lower [52]. In a worldwide survey, none of the 230 patients with Laron had developed cancer, versus 30 cancers among 752 first-degree relatives, mostly heterozygotes; protection appeared to persist even in those treated with IGF-1 [65–67]. These studies compare young patients with relatives and are of limited size, so they do not establish a zero lifetime risk [52, 67].

Longevity is not increased: 70% of deaths of patients over 10 years were due to causes unrelated to age (accidents, alcohol, seizure disorders, cirrhosis), childhood mortality from common diseases was high and vascular mortality was similar to that of relatives (30% versus 33% of deaths) [52, 68]. In a study of 44 Ecuadorian adults (21 with GHRD, 23 relatives), patients had higher LDL cholesterol (140.6 versus 110.5 mg/dL), but lower glucose, insulin and systolic blood pressure (112.1 versus 124.5 mmHg), smaller carotid intima-media thickness, similar pulse wave velocity, a smaller heart with a higher ejection fraction and carotid plaques in 7% versus 36% (non-significant difference) [68]. GHR-null mice live 38–55% longer, an extension not observed in humans [67, 68]. Untreated IGF-1 deficiency, with uncorrected cardiovascular and metabolic problems, may shorten life [67].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Short stature is defined as length or height below the 0.4th percentile, and children below this threshold or whose height crosses successive percentile lines merit investigation [64]. About 75% of referred cases are familial short stature or constitutional delay of growth and puberty; chronic diseases account for about 10%, syndromes 6%, chromosomal anomalies 5%, skeletal dysplasias 1% and GH deficiency or receptor insensitivity 1–2% [64]. Initial assessment includes a three-generation pedigree with parental heights and consanguinity, parents' age at puberty, birth weight, length and head circumference corrected for gestational age, and the growth chart [64]. Target height is calculated, for girls, as [(father's height − 13) + mother's height]/2 ± 9 cm and, for boys, as [(mother's height + 13) + father's height]/2 ± 10 cm; the calculation is misleading when one of the parents also has a genetic cause of short stature, a frequent situation in the dominant forms of this class [2, 64].

GHI should be considered when there is proportionate short stature with slow postnatal growth and low IGF-1 despite normal or high GH, especially with consanguinity, origin in a population with a founder effect (Ecuador, Middle East, Pakistan, Jewish communities of Oriental origin) or affected siblings [2, 4, 62]. A child with a GH deficiency phenotype, hypoglycaemia, micropenis and prominent forehead but raised GH is the classic presentation [2, 61]. Mild forms should be sought in children labelled as having idiopathic short stature, in familial short stature with vertical transmission and in children with a poor response to GH titration, in whom IGF-1 should be repeated [2, 3].

4.2. Clues by entity

Table 4.1. Warning signs by entity [2, 3, 17, 30, 45]

4.3. Emergency signs

Hypoglycaemia in an infant with Laron may be the first manifestation, and hyperinsulinism, deficiencies of GH, adrenocorticotrophic hormone (ACTH) and cortisol and Laron syndrome are among the endocrine causes of neonatal and infantile hypoglycaemia [61]. In the recessive form of STAT5B, dyspnoea, chronic cough or hypoxaemia indicate potentially fatal interstitial lung disease [2, 17]. During mecasermin treatment, seizures or loss of consciousness due to hypoglycaemia, headache with vomiting or visual changes (intracranial hypertension), anaphylaxis and limping or hip or knee pain (slipped capital femoral epiphysis) require immediate assessment [32, 33].

4.4. Newborn screening

There is no newborn screening for this class. Diagnosis depends on growth surveillance and investigation of short stature [3, 64].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

The clinical diagnosis of Laron syndrome rests on three elements: signs of GH deficiency (short stature, reduced growth velocity, delayed bone age) with normal or raised plasma GH; low IGF-1 that does not respond to exogenous GH; and, frequently, low GHBP [4]. The regulatory criteria for SPIGFD differ between jurisdictions (table 5.1), and the −3 SD threshold corresponds to different heights according to national charts: in a 5-year-old boy, 97.0 cm in France, 98.0 cm in Sweden and 95.5 cm in Italy [3]. The narrow margin of these criteria may leave out non-classical forms, including some autosomal dominant ones [3].

The 2016 PES guideline adopts the FDA definition of SPIGFD (height and serum IGF-1 below −3 SD, with normal or raised GH) and emphasises that low IGF-1 and slow growth velocity are not sufficient for diagnosis, because they are common in GH deficiency, malnutrition, chronic corticosteroid therapy, hypothyroidism and chronic disease; in these cases the cause is treated and rhIGF-1 is not used [31]. As there is no single reference test that predicts the response to GH, the guideline suggests a four-step diagnosis (conditional recommendation, moderate-quality evidence on the GRADE scale, Grading of Recommendations, Assessment, Development and Evaluation): (1) screening by auxological parameters and IGF-1 low for age and sex; (2) exclusion of causes of secondary IGF-1 deficiency, with GH stimulation tests for GH deficiency, weight-for-length or BMI charts and, if useful, a 3-day dietary survey for malnutrition, and history, physical examination and liver function tests for liver disease; (3) measurement of GHBP, a very low or undetectable concentration of which suggests Laron syndrome, a normal value being uninformative; (4) IGF-1 generation test and genetic testing, useful but with limitations [31]. Because subtle malnutrition (caloric restriction or reduced protein intake) is enough to lower IGF-1, the guideline advises repeating the measurement after a period of nutritional intervention when this is suspected [31]. Growth failure is postnatal, but may begin before birth in IGF1 defects, in ACLSD and in some patients with Laron; microcephaly, prominent forehead, saddle nose, small chin and high-pitched voice increase clinical suspicion [31].

Table 5.1. Criteria for severe primary IGF-1 deficiency [29, 31–33]

5.2. Biochemistry and interpretation

Assessment of the axis includes GH (stimulated, unless auxology is normal or basal IGF-1 is above the mean; a peak below 7–10 ng/mL suggests GH deficiency, with criteria varying between centres), IGF-1, IGFBP-3, ALS and GHBP [2]. IGF-1 depends on age, sex, pubertal stage, nutritional status, chronic disease and genetic factors; commercial assays have variable sensitivity, norms are scarce in young children and assay recommendations are poorly followed, so it is essential to use a reliable assay with appropriate norms [2, 3]. Before concluding that there is a primary deficiency, malnutrition, liver disease, hypothyroidism, poorly controlled diabetes, chronic inflammatory diseases and corticosteroid therapy must be excluded [2, 7, 33]. Table 2.1 summarises the patterns that guide genetic testing.

GHBP results from proteolytic cleavage of the extracellular domain of GHR; a very low concentration indicates absence of that domain, but variants in the exons encoding the transmembrane or cytoplasmic domains may give normal or high GHBP, so a normal GHBP excludes neither Laron nor post-receptor defects [31]. Among 14 children in the American NCGS (National Cooperative Growth Study) registry with a diagnosis of idiopathic short stature and GHBP below −2 SD, only 4 had GHR variants, and GHBP did not predict the response to GH in children without overt Laron [31].

5.3. IGF-1 generation test

The generation test administers GH over several days and measures the rise in IGF-1, IGFBP-3 and ALS. The criteria defined for classic Laron were a rise in IGF-1 of less than 15 ng/mL and in IGFBP-3 of less than 400 ng/mL, but there is no agreed dose protocol or normative values; even in severe GHI, rises ranged from less than 20 to 58 ng/mL for IGF-1, there is overlap with children with idiopathic short stature and the low-dose protocol did not increase sensitivity [2]. The PES guideline adds that the cut-off points were defined with radioimmunoassays and may not be valid with current assays (double-antibody immunometric assays and mass spectrometry) and that repetition of the test in the same laboratory gave discordant results; in a randomised crossover study of 198 participants, with two 7-day GH regimens and IGF-1 measured on days 5 and 8, measurements correlated between tests, but basal and stimulated values overlapped between GH deficiency and Laron: 6 of 23 children with GH deficiency did not raise IGF-1 adequately and 5 of 22 patients with Laron exceeded the threshold [31]. The test is therefore not recommended in the routine investigation of short stature, and its main value is to confirm severe GHI in patients with a classic phenotype [2, 3]. In the index case of the 6Ω variant, for example, IGF-1 remained below 10 ng/mL after 5 days of GH 0.033 mg/kg/day [51]. In 6Ψ patients, only 1 of 12 tested responded [62].

5.4. Genetic testing

In a classic Laron phenotype, GHR sequencing may be the most economical option; in attenuated or overlapping presentations, a multigene panel or exome is preferable [2]. Panels give greater read depth and coverage, simpler analysis and no incidental findings; exome and genome allow novel genes, pseudoexons and regulatory variants to be found [2]. One panel used in patients with GHI included GHR, IGF1, PAPPA2, STAT5B, IGF1R and IGFALS and genes of the overlapping syndromes (3M, Noonan and Silver-Russell), with about 94% coverage of GHR [51]. Copy number variants are frequent in short stature and comparative genomic hybridisation (CGH) or single-nucleotide polymorphism (SNP) microarray remains the standard, because they are poorly detected by exome; it is mandatory when IGF1R is suspected, because deletion of the whole gene, usually a terminal 15q26 deletion, is an established mechanism [2, 30]. A clinical scoring system assigns one point to each of four criteria (birth weight and/or length, height and head circumference at presentation, IGF-1) and indicates IGF1R testing with 3 or more points, with a sensitivity of about 76% in biased cohorts and about 95% in an independent cohort [17]. For the PES guideline, GHR sequencing confirms Laron when GHBP is very low or undetectable, gene-by-gene testing is limited to known causes and exome allows novel causes to be identified; genetic testing is desirable whenever diagnostic uncertainty affects treatment [31].

The yield is limited. Between 30% and 48% of GHI cases have a genetic diagnosis; about 60% of children with GHI, IGF-1 deficiency and short stature have no variants in GHR, STAT5B or IGF1; and in the European registry only 13% of children treated with rhIGF-1 had a confirmed GHR variant or deletion [2, 3, 17]. Among 80 children with hypoglycaemia on treatment, 32 underwent genetic testing and 21 of them (65.6%) had Laron, which suggests underdiagnosis [28]. A negative test does not exclude the diagnosis: deep intronic variants (6Ψ, 6Ω) escape exonic panels, deletions require copy number analysis and many missense variants remain VUS for lack of functional proof [17, 51]. Heterozygous GHR variants occur in 5–15.5% of children with idiopathic short stature, but many (for example G168G and I526L, in mature protein numbering, the latter NM_000163.5:c.1630A>C p.(Ile544Leu), benign in ClinVar, and several intronic ones) are equally frequent in controls and should not be taken as causal without proof [2, 40]. A genetic diagnosis is not a prerequisite for rhIGF-1 and did not alter the response in the European registry [3]. In countries with limited access, sending samples to foreign laboratories delays diagnosis [3].

The report should state the gene, the versioned MANE (Matched Annotation from NCBI and EMBL-EBI) reference transcript (GHR NM_000163.5; STAT5B NM_012448.4; IGFALS NM_004970.3; IGF1 NM_000618.5; PAPPA2 NM_020318.3; IGF1R NM_000875.5), the HGVS nomenclature, the correspondence with the historical mature-protein nomenclature where applicable, zygosity and the class according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); segregation testing in the parents is essential to confirm trans phase in compound heterozygotes and to classify de novo variants [46, 50].

5.5. Functional tests

In vitro ternary complex formation and ALS Western blot demonstrate the defect in ACLSD; free and bioactive IGF-1, which are not measured routinely, reveal the PAPPA2 defect; GH-induced STAT5B phosphorylation and flow cytometry of IGF1R expression and signalling in mononuclear cells or fibroblasts exist in a research setting [17, 54, 58]. In STAT5B deficiency, immunological assessment includes immunoglobulins with IgE, lymphocyte subsets with regulatory T-cell count, autoantibodies and chest imaging or lung function tests [54].

5.6. Practical algorithm

1. Child with proportionate short stature and reduced growth velocity: exclude chronic disease, malnutrition, hypothyroidism, coeliac disease and chromosomal anomaly (karyotype or microarray in all girls and in boys with dysmorphic features or intellectual disability) [64].
2. Measure IGF-1, IGFBP-3, ALS and GHBP and assess GH secretion; if malnutrition is suspected, repeat IGF-1 after nutritional intervention; a very low or undetectable GHBP points to GHR [2, 31].
3. Low IGF-1 with normal or high GH: apply the criteria of table 5.1 and request a GH–IGF-1 axis panel with copy number analysis, or GHR sequencing if the phenotype is classic; consider the generation test only to confirm severe GHI [2, 3].
4. Negative panel with a suggestive phenotype: exome or genome with analysis of deep intronic regions of GHR [2, 51].
5. Normal or high IGF-1 with IUGR and microcephaly: microarray and IGF1R sequencing; very high total IGF-1 with high IGFBP-3 and ALS: PAPPA2 [30, 45].
6. Immune or pulmonary signs: STAT5B and immunological assessment [54].

5.7. Prenatal and preimplantation diagnosis

Prenatal diagnosis is possible when the familial variant is known, and serial ultrasound scans allow fetal growth to be monitored [64]. In forms with postnatal onset (GHR, STAT5B, IGFALS, PAPPA2), fetal growth is normal and ultrasound does not help; in forms with IUGR (IGF1, IGF1R), the growth restriction is non-specific [2, 17]. Preimplantation genetic testing applies to known pathogenic variants (section 8).

6. Differential Diagnosis

6.1. Table of types and differentials

Table 6.1. Entities of the class and main differentials [2, 3, 7, 17, 64, 65, 69, 70]

6.2. GH deficiency and other endocrine causes

GH deficiency shares the clinical phenotype with Laron, which was considered clinically indistinguishable from congenital GH deficiency; what separates the two is GH, low in deficiency and normal or high in insensitivity, and the IGF-1 response to GH [4, 7]. Septo-optic dysplasia (with GH deficiency in 80% in one series) and other midline anomalies are associated with GH deficiency and not with insensitivity [64]. In patients with GH1 deletion who develop neutralising antibodies, GHI is acquired and mecasermin has an approved indication in the USA [2, 33].

6.3. Syndromes with phenotypic overlap

Silver-Russell syndrome has prenatal and postnatal growth restriction, relative macrocephaly, triangular face and asymmetry in about half of cases; up to 60% have hypomethylation of ICR1 at 11p15 and 5–10% maternal uniparental disomy of chromosome 7 [64]. The tendency to fasting hypoglycaemia extends from 6 months to 3 years, which requires frequent meals and glucose supply during intercurrent illness, and GH is beneficial even without GH deficiency, unlike what happens in insensitivity [73]. Children with 11p15 hypomethylation have higher IGF-1 and IGFBP-3 than those with disomy 7 and than other SGA-born children, suggesting some IGF-1 resistance, without IGF1R defects [2]. Paternally inherited IGF2 variants give a Silver-Russell picture (14 of 14 patients met the Netchine-Harbison criteria), with frequently high IGF-1 (1.5 ± 2.5 SD) [17]. In IGF1R variants, the combination of IUGR, microcephaly and high IGF-1 also resembles Silver-Russell, but without the relative macrocephaly [30, 59].

3M syndrome (CUL7 65–70%, OBSL1 25–30%, CCDC8 about 5%) shares with classic GHI the prominent forehead, depressed nasal bridge, temporal hair thinning and high-pitched voice; GH is normal or high, IGF-1 normal or low and the response to GH typically poor, with evidence of partial resistance to GH and IGF-1 [2, 69]. Birth length at term is usually 35–42 cm, bone age is delayed and there is no evidence that GH is effective in 3M [74]. Noonan syndrome (incidence 1/1000 to 1/2500) has short stature in up to 80%; PTPN11, altered in about 50%, encodes SHP-2, which dephosphorylates STAT5B, and patients with a PTPN11 variant have lower IGF-1 and a poorer response to GH, but the first-line treatment is GH [2, 3]. In another source, short stature of postnatal onset occurs in about 50% of patients, with abnormalities of IGF-1, IGFBP-3 and GH secretion and mild GH resistance that may reduce the response to somatropin; mean adult height is 162.5 cm in men and 151 cm in women (2nd percentile), and more than half of women and about 40% of men remain below the 3rd percentile [75, 76]. The difference between 50% and 80% reflects the definitions and series of each source.

11q deletion (Jacobsen syndrome) includes IGF-1 deficiency among the occasional anomalies, and the 15q26 deletion that includes IGF1R may mimic Silver-Russell [59, 77]. SHOX haploinsufficiency (2.4–7% of children with idiopathic short stature), Turner syndrome, skeletal dysplasias, Floating-Harbor syndrome, DNA repair defects and microcephalic primordial dwarfisms complete the differential of short stature [64].

6.4. Immunodeficiencies with growth delay

STAT5B deficiency must be distinguished from other immunodeficiencies with growth failure. In STAT3 gain of function, an international cohort of 191 patients had a median onset at 2.3 years, lymphoproliferation in 73% and autoimmune cytopenias in 67%, with growth delay, enteropathy and endocrine autoimmunity; IGF-1 is low with normal GH, but three patients treated with GH responded well, and the growth failure was attributed mainly to chronic inflammation [2, 70]. IKBKB and IκBα variants and PRKCA overexpression are associated with reduced GH sensitivity with immunodeficiency [2, 3]. A completed trial evaluated IGF-1 in the growth failure of X-linked severe combined immunodeficiency, with GH resistance [78].

6.5. Acquired GH resistance

Malnutrition, inflammatory bowel disease, severe or catabolic illness, liver disease and poorly controlled type 1 diabetes cause high GH, variable IGF-1, low GHBP and low or normal IGFBP-3; in severe type 1 diabetes (Mauriac syndrome, with hepatomegaly and cushingoid features) adequate insulin therapy reverses the growth failure [7]. Antibodies directed against GHR, mainly against the extracellular domain, may have an antagonist or agonist effect [7]. Malnutrition is a common cause of low IGF-1 and must be excluded before diagnosing a primary deficiency [2, 33]. In congenital disorders of N-glycosylation, such as ALG1-CDG (autosomal recessive, with intellectual disability, hypotonia, microcephaly and seizures), serum IGF-1 and IGFBP-3 may also be low; isoelectric focusing of serum transferrin (type 1 pattern) guides the diagnosis [79].

7. Treatments and Risk Management Strategies

7.1. Principles

The aim of treatment is to bring adult height closer to the target range and, beyond height, to improve metabolic health, body composition and psychosocial well-being [3]. In complete GHI, exogenous GH is ineffective: high doses of somatropin raise IGF-1 slightly and transiently, without normal growth, and rhIGF-1 is the only effective option [7, 32, 80]. In partial forms (IGF-1 resistance, ACLSD, some heterozygotes), somatropin may have an effect, although a variable one [2, 35, 58]. Because lost height is not recovered and early initiation was the only significant predictor of response in the European registry, treatment should begin as soon as the diagnosis is established [3, 48].

The 2016 PES guideline, developed using the GRADE method, included rhIGF-1 in growth treatment recommendations for the first time and is the reference for dosing in this class; the recommendations on primary IGF-1 deficiency are in table 7.1 [31]. The authors' commentary points out that, in primary IGF-1 deficiency, rhIGF-1 had the strongest level of evidence of efficacy on height, with hypoglycaemia as the main safety concern [81]. Doses from the FDA and EMA labels are cited for comparison (table 7.2).

Table 7.1. PES 2016 guideline recommendations for primary IGF-1 deficiency [31]

The preference for the lower dose is based on a trial in Ecuadorian patients homozygous for the same GHR variant: 14 received 120 µg/kg and 7 received 80 µg/kg twice daily, according to the time of entry into the study; gains in growth velocity and height SD were similar, but the high-dose group had accelerated skeletal maturation in the third year, with increased body fat percentage and adrenal growth, which may compromise the gain in adult height [31]. The guideline calls for randomised trials to establish the dose that best balances benefit and risk [31].

7.2. Mecasermin (Increlex®)

Mecasermin is recombinant human IGF-1 produced in Escherichia coli, with 70 amino acids, three disulphide bridges and 7649 Da, with a sequence identical to that of endogenous IGF-1 (ATC code H01AC03) [32]. It is presented in a 40 mg/4 mL (10 mg/mL) multidose vial, with 9 mg/mL benzyl alcohol as preservative, and is stored at 2–8 °C, protected from light, for up to 30 days after opening [32, 33]. In SPIGFD, IGFBP-3 is reduced and IGF-1 clearance increased; the terminal half-life of total IGF-1 after 0.12 mg/kg subcutaneously was 5.8 hours, and clearance is inversely proportional to IGFBP-3 [32]. The insulin-like action (increased muscle glucose uptake through IGF1R) explains the hypoglycaemia [28]. The non-proprietary name at INFARMED (Portuguese National Authority of Medicines and Health Products) is "mecassermina" [82].

Table 7.2. Mecasermin dosing: PES 2016 guideline (reference) and labels (comparison) [31–33, 83]

The guideline maintenance dose (80–120 µg/kg, that is, 0.08–0.12 mg/kg twice daily) falls within the range of both labels, but there are three differences: the guideline prefers the lower dose, whereas the European SmPC and the long-term trial describe a greater response with 120 µg/kg; the 150–180 µg/kg once-daily regimen is outside the conditions of both labels, which provide for two daily administrations; and the guideline sets the injection 20 minutes after the meal, whereas the FDA allows ± 20 minutes and the EMA "shortly before or after" [31–33, 80]. The guideline does not set an initial dose, so titration from 0.04 mg/kg follows the labels [31–33]. The regimens described in the literature are divided into two daily doses of 40–120 µg/kg or a single daily dose of 150–200 µg/kg; the twice-daily regimen arose from a pharmacokinetic study that showed faster IGF-1 turnover in Laron than in healthy volunteers, and the once-daily regimen is advocated by some groups, who describe similar velocities with fewer adverse effects [31].

In the trials, doses ranged from 60 to 120 µg/kg twice daily, with a dose-dependent response that was greater with 120 µg/kg twice daily [32, 80]. In the European registry, the median initial dose was 40 µg/kg twice daily, the same in children with and without Laron after titration [48]. With syringes graduated in units, the dose is converted using the formula weight (kg) × dose (mg/kg) × 1 mL/10 mg × 100 units/mL [33]. In the United Kingdom, initiation is often done with an admission of about 5 days when difficulty in glycaemic control is anticipated; in the USA, Poland and Sweden, it is done as an outpatient [3].

Contraindications differ between labels. The FDA contraindicates mecasermin in hypersensitivity, closed epiphyses and active or previous malignant neoplasia; the EMA contraindicates it in hypersensitivity, active or suspected neoplasia, any condition that increases the risk of benign or malignant neoplasia and in preterm infants and newborns [32, 33]. Mecasermin does not replace GH in GH indications and is not indicated in secondary IGF-1 deficiencies (GH deficiency, malnutrition, hypothyroidism, chronic corticosteroid therapy) [33].

7.3. Adverse effects and their management

Hypoglycaemia. This is the most frequent adverse effect. In the American clinical programme (71 patients, 274 patient-years), it occurred in 42%, mostly mild or moderate, with severe hypoglycaemia in 5 patients and seizures or loss of consciousness in 4; 47% of those who had it had hypoglycaemia before treatment, and episodes were concentrated in the first month and in the youngest children [33]. In the European pool of 413 trial patients, the frequency was 28%, with 6 hypoglycaemic seizures [32]. In the Eu-IGFD registry (304 patients, December 2008 to May 2021), 26.3% had treatment-induced hypoglycaemia and 2.6% severe hypoglycaemia, with 0.11 events and 0.01 severe events per patient-year; prior hypoglycaemia and a diagnosis of Laron were the predictors, and episodes did not reduce height gain [28]. The difference between trials (49% in the long-term study) and post-marketing (28%) is attributed to glycaemic monitoring and education [3, 80]. A narrative review gives 8%, a value that does not match the labels and reflects other definitions and populations [7]. Prevention is based on giving the dose with a meal, omitting it if the child does not eat, not giving it after exercise, avoiding high-risk activities (driving, sport) in the following 2–3 hours at the start, measuring preprandial blood glucose until the dose is established, reducing the dose if there is hypoglycaemia despite adequate intake and teaching parents the signs, symptoms and treatment, including glucagon; anyone who has had severe hypoglycaemia should have glucagon available [28, 32, 33]. The PES guideline, which classifies administration after the meal and family education as a strong recommendation with high-quality evidence, adds reinforced monitoring during intercurrent illness, with a home glucometer, and points out that hypoglycaemia is also a feature of Laron syndrome itself, attributed to the profound loss of GH action [31]. In acute overdose, oral glucose or food is given and, if there is loss of consciousness, intravenous glucose or parenteral glucagon [32]. Some patients with Laron have asymptomatic hypoglycaemia before treatment and postprandial hyperglycaemia on continuous monitoring, which rhIGF-1 improves [28].

Intracranial hypertension. This occurred in 3 patients in the American programme (two resolved without interruption; in the third, mecasermin was resumed at a lower dose without recurrence) and in 4 of the 413 European patients (0.96%), all treatment-naive and aged 7–9 years, without sequelae [32, 33]. Fundoscopy is performed at the start, periodically and in the presence of headache, nausea, vomiting or visual changes, and dosing is interrupted if there is papilloedema [32, 33]. A child with PAPPA2 deficiency had intracranial hypertension that required treatment to be stopped [2].

Lymphoid tissue hypertrophy. Tonsillar hypertrophy appeared in 15% (11/71) in the first 1–2 years in the American programme, with tonsillectomy or adenotonsillectomy in 7 and obstructive sleep apnoea in 3, resolved after surgery; in the European pool, in 9% (38/413), with snoring in 7% [32, 33]. Periodic examinations are recommended to detect snoring, sleep apnoea and otitis media with effusion [32, 33].

Other effects. Lipohypertrophy and hypertrophy at the injection site (17–32%), avoidable by rotating sites; headache (44% in the European pool), vomiting, otitis media and middle ear effusion, hearing loss, arthralgia and pain in the extremities; thymic hypertrophy; heart murmur and, rarely, cardiomegaly, ventricular hypertrophy and mitral and tricuspid valve insufficiency; thickening of facial soft tissues; rapid growth of kidney and spleen in the first years, with normal renal function; mild elevations of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH); raised cholesterol and triglycerides before and during treatment; gynaecomastia; melanocytic naevi; alopecia and change in hair texture [32, 33, 80]. The EMA recommends an echocardiogram before starting in all patients and at the end of treatment [32]. Slipped capital femoral epiphysis, with or without osteonecrosis, and progression of scoliosis may occur with rapid growth [32, 33]. Anaphylaxis was estimated at 0.3% post-marketing, with urticaria, angioedema and dyspnoea [33]. Anti-IGF-1 antibodies appear in some patients without attenuating growth; testing for them is warranted when there is an allergic reaction, unexpectedly high IGF-1 after injection or absence of response without a cause [32]. For the PES guideline, the remaining risks are similar to those of GH (intracranial hypertension, slipped capital femoral epiphysis and progression of scoliosis), with contraindication in active neoplasia, to which are added lymphoid tissue hypertrophy, hypersensitivity and reactions to the benzyl alcohol in the diluent [31].

Neoplasms. There have been post-marketing reports of benign and malignant neoplasms, some rare in childhood, mainly in patients with predisposing genetic conditions, with doses above those recommended or with IGF-1 above the reference range; a causal relationship has not been established [32, 33]. In the European registry (242 patients) there were 3 benign neoplasms (naevi) and 1 fatal myelodysplastic syndrome in a patient with multiple prior comorbidities [48]. If a neoplasm appears, treatment is permanently discontinued [32, 48].

Monitoring of response. The EMA recommends reconsidering treatment if there is no response after one year [32]. Growth velocity is the criterion of success, and bone age advanced in parallel with chronological age (5.3 years in 4.9 years) [32, 33].

7.4. Evidence of efficacy

Table 7.3. Studies and registries of rhIGF-1 in SPIGFD [31–33, 48, 56, 62, 80, 83]

These data come from open-label studies, a programme with a single controlled arm and registries, without long-term randomised comparison with no treatment; the groups differ in age, severity and genotype, so they cannot be compared directly with each other [33, 48]. The PES guideline also notes that the data come from four main groups (Israel, Ecuador, USA and Europe), with overlapping publications of the same patients, that puberty and gonadotrophin-releasing hormone agonists confound the results, that Tanner stage was not recorded although growth velocity was the main outcome, that there may be publication bias and that most patients had Laron, so the optimal dose may differ in other forms [31]. The gain in velocity is concentrated in the first year and declines thereafter, remaining above baseline for 6–8 years, and adult height generally remains below the normal range, with a mean gain of 13 cm [32, 80, 83]. First-year velocity with rhIGF-1 (6.9 cm/year; 95% CI 6.5–7.2; n=144) is lower than with GH in GH deficiency (8.67 cm/year; n=465), which should not be a reason to refuse treatment [3]. Children with Laron in the registry started treatment at a mean age of 6.07 years and the others at 8.44 years; younger age was the only independent predictor of response (odds ratio 0.75 per year; 95% CI 0.65–0.87) [48]. Gonadotrophin-releasing hormone (GnRH) analogue, added in 9 patients with puberty at a normal age who wished to prolong the growth period, did not improve adult height [31, 83]. Two Ipsen trials outside classic SPIGFD (less severe primary IGF-1 deficiency, n=114, and the GH + rhIGF-1 combination, n=106) were terminated, and a third in short stature with IGF-1 deficiency (NCT00125190; n=45; 2005–2009) has results in the registry [78]. A trial of the rhIGF-1/rhIGFBP-3 complex (mecasermin rinfabate; Insmed) in GHI was completed without results in the registry (NCT00368173), and the American IGF-1 deficiency registry (NCT00747604; 1378 patients; 2006–2014) was terminated [78].

7.5. Regulatory status

Table 7.4. Regulatory status of mecasermin [3, 27, 32, 33, 82, 84]

7.6. Treatment by entity

Choice between GH and rhIGF-1. The PES guideline recommends (strong recommendation, low-quality evidence) a therapeutic trial of GH before rhIGF-1 in IGF-1 deficiency without an established cause, and direct initiation of rhIGF-1 in defects that do not respond to GH: very low or undetectable GHBP and/or GHR variants associated with Laron, GH1 deletion (GH deficiency type 1A) with neutralising antibodies, STAT5B variants and IGF1 deletion or variant [31]. If GH is effective, as in partial insensitivity, it is preferable for four reasons: first-year velocity with GH in GH deficiency (10–12 cm/year) exceeds that of rhIGF-1 in primary IGF-1 deficiency (8–9 cm/year), which is attributed to the direct actions of GH on the growth plate; GH is given as one daily injection and rhIGF-1, in the USA, as two; GH does not cause hypoglycaemia; and GH also raises IGFBP-3, which is more physiological and theoretically favourable with regard to oncological risk [31]. Treating a child with sufficient GH secretion with rhIGF-1 may suppress endogenous GH, reduce IGF-1 production and the delivery of GH to bone, and there are no data supporting rhIGF-1 in idiopathic short stature [31]. Kowarski syndrome (bioinactive GH due to a GH1 variant), with low IGF-1 and normal or slightly increased GH secretion, responds to GH [31].

Laron syndrome. Mecasermin is the treatment of choice and the European indication explicitly names variants of the GH receptor [32]. Patients with Laron have more hypoglycaemia, before and during treatment, and should be closely monitored [28]. rhIGF-1 also improves the facial features and, in the first studies, increased head circumference, weight and lean mass and reduced subcutaneous fat [4, 7]. In the European registry, BMI rose by about 1.0 SD over 4–5 years in children with Laron [48].

Non-classical forms of GHR. The response to GH is not sustained; rhIGF-1 accelerated growth in children treated early (for example, from 4 to 8.1 cm/year) and the combination of GH with rhIGF-1, approved by neither the FDA nor the EMA, normalised height in one patient [2]. In 6Ψ patients, rhIGF-1 (mean dose 114 µg/kg twice daily) gave results similar to those of other homozygous GHR defects, with no correlation with age at initiation [2, 62]. Many patients with mild forms do not meet the label criteria; in a controlled trial in children with height and IGF-1 ≤ −2 SD, rhIGF-1 raised first-year velocity to 7.9 ± 1.4 cm/year versus 5.2 ± 1.0 in untreated children, with fewer adverse effects than in classic GHI, and the combination of rhIGF-1 (150 µg/kg/day) with GH (45 µg/kg/day) gave 11.2 ± 2.1 versus 9.3 ± 1.7 cm/year with GH alone [2]. These uses are outside the conditions of the labels.

STAT5B deficiency. Patients who meet the biochemical criteria fall within the label indication, but the response is smaller than in GHR defects; in the three siblings with p.Trp631*, started on 40 µg/kg twice daily and titrated to 110–120 µg/kg twice daily, severe lipohypertrophy, insufficient weight gain, hypoglycaemia and reduced adherence limited the response in the youngest [54, 56]. GH was uniformly ineffective in treatments of 1 to 4 years [2]. The immune and lung disease is managed by immunology and respiratory medicine: corticosteroids and oxygen temporarily stabilise lung function, one patient underwent lung transplantation and there is no established specific immunological therapy [2, 54]. The dominant-negative forms have near-normal immunity; a patient with controlled autoimmune thyroiditis and coeliac disease responded poorly to GH [46].

IGF-1 deficiency. Mecasermin is the logical replacement and a child with a biallelic variant who meets the criteria falls within the indication; in partial IGF1 deletion, velocity increased from 3.8 to 6.6 cm/year in the first year [21]. GH had no effect in the homozygote (2.5 and 2.2 cm/year before and after); among heterozygotes, one did not respond and two gained +1.0 and +1.5 SD over 2 years [2].

Acid-labile subunit deficiency. There is no genotype-specific approved therapy. Most patients have height above −3 SD and do not meet the mecasermin indication; somatropin, within the indication of idiopathic short stature (height ≤ −2.25 SD), had a modest and variable response, possibly related to residual ALS expression [2, 57, 58]. For that indication, the PES guideline suggests starting GH at 0.24 mg/kg/week, with some patients needing up to 0.47 mg/kg/week, and reassessing the benefit on height and the psychosocial impact 12 months after initiation and dose optimisation (conditional recommendations, low-quality evidence); the Genotropin® label allows up to 0.47 mg/kg/week [31, 34]. The guideline also states that ACLSD responds poorly to both GH and rhIGF-1 and that growth failure is mild despite very low IGF-1 [31]. Puberty, glucose tolerance and insulin sensitivity should be monitored [57].

Dauber-Argente type short stature. In four patients with growth potential, rhIGF-1 gave +0.4 SD in the first year in three, resolved insulin resistance and increased mineral density and trabecular bone quality; the fourth had intracranial hypertension and stopped [2, 17]. This use is outside the approved indication, because total IGF-1 is not low.

IGF-1 resistance. Treatment is somatropin, within the phenotypic indications of SGA without catch-up by 2 years (up to 0.48 mg/kg/week in the Genotropin® label) or idiopathic short stature [30, 34]. The reference age for lack of catch-up in SGA is 2 years in the American label and 4 years in the United Kingdom licence, which also covers Turner syndrome, GH deficiency and SHOX deficiency, with no clear benefit in most syndromes and skeletal dysplasias [34, 64]. In a cohort of 23 carriers compared with 34 SGA children, first-year gain was smaller (0.29 versus 0.65 SD), poor responders were three times more frequent (53% versus 17%) and insulin resistance increased during treatment; good responders caught up to the level of SGA children, so success should be reassessed periodically and glucose and insulin monitored [35]. IGF-1 is already high before treatment and should be monitored [17]. Mecasermin is not indicated [30].

7.7. Developments in the last 12 months

In the last 12 months no new approved drug and no active clinical trial specific to the disorders of this class appeared on ClinicalTrials.gov (search of 31/10/2026, which does not prove absence) [78]. On the regulatory front, the US label in force became that of Eton Pharmaceuticals (18/05/2026), without change in indication or dose relative to that of 2025 [33]. The Eu-IGFD global safety registry (NCT00903110), sponsored by Esteve, continues to recruit (update of February 2026; expected end December 2027; 500 patients planned) [78]. For the differential with STAT3 gain of function, a phase 1/2 trial of the JAK inhibitor upadacitinib in JAK/STAT disorders with activating variants has been registered (NCT07670156; expected start October 2026; 30 patients), still without results — level of evidence: registered trial [78]. The sources consulted do not describe human studies of therapies targeted at the molecular mechanism of any of the entities in the class [2, 17].

7.8. Special populations and situations

Infants. Mecasermin is not recommended below 2 years, and benzyl alcohol may cause "gasping" syndrome in newborns and preterm infants and toxic reactions up to 3 years [32, 33]. In infants with Laron, prevention of hypoglycaemia is based on regular feeding [28, 61].

Pregnancy and lactation. Mecasermin is not indicated after epiphyseal closure. The EMA advises against its use in pregnancy and breastfeeding and recommends a negative pregnancy test and adequate contraception in all women of childbearing potential; the FDA notes the absence of human data and of embryofetal abnormalities in rats and rabbits at exposures of 11 and 3 times the maximum human dose [32, 33]. Women with Laron have preserved fertility [3].

Diabetes and surgery. In diabetic patients, insulin or other hypoglycaemic agents may need to be reduced [32]. Before surgery or fasting, the dose should be omitted whenever the child cannot eat, as the label requires [32, 33]. Tonsillar and adenoidal hypertrophy may require tonsillectomy and adenoidectomy [33]. The sources consulted do not describe specific anaesthetic recommendations for the class.

Transition to adulthood. Treatment ends with epiphyseal closure [33]. In adulthood, truncal obesity, raised LDL, hip degeneration and problems of mobility and social integration persist; there are no data justifying rhIGF-1 in adults [3, 4, 68]. In STAT5B deficiency, immunological and pulmonary surveillance continues throughout life [2].

Psychosocial support. Short children more often suffer from low self-esteem, bullying and discrimination, with effects on choice of partner and employment; families need information, genetic counselling and psychological support, and treatment with two daily injections places a burden on family life [3].

7.9. Divergences between sources

The main divergences concern the IGF-1 threshold (≤ −3 SD in the USA and < 2.5th percentile in the EU), the initial dose (0.04–0.08 versus 0.04 mg/kg), the indication in GH1 deletion with antibodies (USA only), the echocardiogram and pregnancy test (EU only) and the oncological contraindications (malignant neoplasia in the USA; any condition that increases the risk of neoplasia in the EU) [32, 33]. The role of the IGF-1 generation test also differs: the EMA accepts it as an aid to diagnosis, the PES guideline considers it useful but limited, and experts consider it useful only to confirm severe GHI [2, 3, 31, 32]. Between the PES guideline and the labels, the differences lie in the guideline's preference for 80 µg/kg twice daily, in the 150–180 µg/kg once-daily regimen used outside the USA (outside the conditions of the labels), in the timing of the injection (20 minutes after the meal in the guideline; ± 20 minutes in the FDA label; shortly before or after in the EMA label) and in the prior trial of GH in IGF-1 deficiency without an established cause, which the labels do not provide for; the guideline uses the FDA −3 SD threshold for IGF-1, more restrictive than the EMA 2.5th percentile [31–33]. The 2023 multi-stakeholder panel called for an updated diagnostic and treatment consensus and an algorithm for IGF-1 deficiencies [3].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by entity

The recessive forms (classic GHR and pseudoexons, STAT5B GHISID1, IGF1, IGFALS, PAPPA2 and the rare biallelic IGF1R) have a recurrence risk of 25% for each pregnancy of a carrier couple; consanguinity, present in 95% of 6Ψ patients and in several Laron and STAT5B families, increases the probability of homozygosity [2, 4, 62]. Compound heterozygotes are frequent in populations without consanguinity, as shown by the Italian siblings with 6Ω and R43X and the Spanish patients with two different GHR variants [5, 51]. The dominant forms (dominant-negative GHR, STAT5B GHISID2, heterozygous IGF1R and 15q26 deletion) carry a 50% risk for the offspring of a carrier; they may arise de novo, as in the mother of Ayling's proband and in a dominant-negative STAT5B family [4, 11, 46]. In GHISID2, carrier parents had a milder phenotype (height about −1.5 SD), which illustrates variable penetrance of some features [11].

8.2. Heterozygotes and dosage effect

Heterozygosity is not always neutral. Carriers of E180splice do not differ significantly from non-carriers in height (or differ by about 0.55 SD in a larger analysis) or in biochemical markers [2, 5]. IGFALS carriers lose about 1.0 SD [2, 17]. IGF1 carriers have smaller head circumference, birth weight and height, and it has been proposed that haploinsufficiency of maternal origin is more penalising (about 2 SD) than of paternal origin (1 SD) [2]. Carriers of recessive STAT5B variants have low-normal height and no immune disease [2]. These data should be explained to short parents and siblings of a patient, who may benefit from auxological assessment.

8.3. Cascade testing and testing of minors

Once the variant has been identified, testing is offered to the parents (to confirm trans phase or de novo origin), to siblings with slow growth and, in dominant forms, to short relatives [46, 64]. Testing of minor siblings is justified when there is direct medical benefit, such as early initiation of rhIGF-1, which improves the response, or immunological surveillance in STAT5B deficiency [2, 48]. Carrier detection in large families is possible provided the variant is known [64].

8.4. Prenatal and preimplantation diagnosis

Prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible when the familial variants have been identified and classified as pathogenic [64]. Deep intronic variants require the laboratory to confirm its ability to detect them in fetal or embryonic material [51]. In forms with postnatal onset there is no prenatal ultrasound sign, and in forms with IUGR the restriction is non-specific [17].

8.5. Content of counselling

Counselling covers the mode of inheritance and recurrence risk, variability of expression within the same family, the availability and limitations of treatment (mean adult height gain of about 13 cm with rhIGF-1, two daily injections, risk of hypoglycaemia), normal fertility in Laron and ACLSD, the immune and pulmonary risks of STAT5B deficiency and the data on cancer and diabetes in Laron, without presenting them as an individual guarantee [3, 52, 58, 83]. Parental heights should be interpreted with care, because the target height calculation is misleading when one parent has the same genetic cause [64].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

The prevalence of Laron syndrome recorded in Orphanet for Europe is 1–9 per million (mean value 0.3/100,000), originating from a 2003 EMA document; the value of 4.86/100,000 for China comes from a hospital survey in Shanghai and does not represent the general population [6, 27]. Primary IGF-1 deficiencies in the European Union are estimated at fewer than 2 per 10,000 people, a regulatory estimate that includes forms without a genetic cause [3, 28]. The proportion of 1.2% (30/2546) with SPIGFD among children referred to a French paediatric endocrinology centre between 2004 and 2009 measures frequency in a referred population, not prevalence; only 0.2% were considered eligible for rhIGF-1 [29]. For the remaining entities there are only case counts: about 10 families with recessive STAT5B (Orphanet), 11 homozygous patients and 11 with dominant-negative variants in the series reviewed, about 5 families with recessive IGF1, more than 62 patients with ACLSD, 5 children from 2 families with PAPPA2 in the initial descriptions, and about 60 IGF1R variants with a cohort of 23 carriers in 8 centres [13, 17, 20, 30, 35, 45]. Laron had about 60 cases published before 1990, half in Israel, and several hundred by 2021; a 2011 survey estimated that it had included 30–40% of the world population with Laron [4, 17, 67]. Non-classical forms are probably more frequent than classical ones, and heterozygous GHR variants probably explain no more than 5% of idiopathic short stature [2].

9.2. Founder populations and geography

Laron is concentrated in populations with consanguinity and in isolates. In Ecuador, in the provinces of Loja and El Oro, most patients are homozygous for E180splice; the cohort followed since 1988 includes 99 patients, and the community probably descends from Jews converted ("conversos") during the Inquisition; in Loja a skewed sex ratio was observed (19 women to 2 men), unlike El Oro (14:12) [4, 17, 52]. In Israel, the first patients were Oriental Jews, including families of Yemenite origin [2, 4]. A splice variant at codon 236 explains the concentration of the disease in an isolate in the Bahamas, attributed to an English settler [4]. The 6Ψ pseudoexon is concentrated in consanguineous Pakistani families, and 6Ω in two families from the same locality in Campania, Italy [51, 62]. In Europe, Spanish patients with GHR variants, the Spanish and Palestinian families with PAPPA2 and Turkish families and a Kurdish family in the Netherlands with IGFALS have been described [2, 5, 45]. In the USA, an African-American patient with R217X (NM_000163.5:c.703C>T p.(Arg235Ter); ClinVar 8639) and a Hispanic patient with a dominant-negative GHR variant have been described [2, 5, 40].

9.3. Portugal and Brazil

There are no Portuguese series in the sources consulted. Mecasermin is authorised and marketed in Portugal, as a medicine for exclusive hospital use [82]. In Brazil, the sources describe a case of Laron with consanguinity and the GHR variant IVS6 −1 G>T (NM_000163.5:c.619-1G>T; ClinVar 8642) and the participation of a São Paulo centre in the Latin American ACLSD series; mecasermin does not appear in ANVISA's open registration data [5, 40, 58, 84]. The lack of approval in most of South America limits access to treatment [3].

9.4. Special populations and access

Access to genetic diagnosis and rhIGF-1 is unequal: in many low- and middle-income countries there is no local genetic testing nor approval of the medicine, and managed access programmes may be suspended; several patients from the Middle East live in disadvantaged socioeconomic settings [3]. National growth charts should be used to calculate height SD, because the same threshold corresponds to different heights in different countries [3].

9.5. Reference networks and patient associations

In Europe, patients are followed in the centres of Endo-ERN, a network of more than 100 reference centres in 27 Member States and Norway, within thematic group MTG5 (growth and genetic obesity syndromes) [36]. Patient associations: MAGIC Foundation (USA; www.magicfoundation.org) and Child Growth Foundation (United Kingdom; childgrowthfoundation.org), the latter also mentioned together with the Restricted Growth Association (www.restrictedgrowth.co.uk) [64, 85, 86]. The Eu-IGFD global registry collects safety and efficacy data on rhIGF-1 [48, 78].

10. Illustrative Clinical Case

Cottrell and colleagues described in 2021 a boy, the second child of non-consanguineous white parents without dysmorphic features, born at 37 weeks with normal weight (−0.4 SD) [51]. Growth failure was noticed at 5 months and, at 1.7 years, he measured 61 cm (−7.4 SD), with normal BMI (16.5; −0.6 SD) and relative macrocephaly (head circumference −1.2 SD); he had the facial features of Laron (midface hypoplasia, depressed nasal bridge and prominent forehead), delayed tooth eruption, small hands and feet, micropenis, bilateral cryptorchidism and a hypoplastic scrotum [51]. The mother's and father's heights were −2.0 and −1.5 SD, with no family history of growth failure [51]. Random GH was 38 µg/L, IGF-1 below 10 ng/mL, IGFBP-3 below 80 ng/mL, and ALS and GHBP were undetectable; in a 5-day generation test with GH 0.033 mg/kg/day, IGF-1 remained below 10 ng/mL [51].

A capture panel of the genes of the GH–IGF-1 axis and the overlapping syndromes, which covered about 94% of the genomic region of GHR, including introns, identified in the homozygous state the deep intronic GHR variant NM_000163.5:c.618+836T>G, inherited from heterozygous parents, which activates the 151 bp 6Ω pseudoexon and produces a truncated receptor lacking the transmembrane and intracellular domains [50, 51]. He started mecasermin 120 µg/kg subcutaneously twice daily at 2.1 years; he had many episodes of hypoglycaemia that required continuous glucose monitoring for 6 months and a mild, isolated and persistent rise in thyrotrophin (TSH) (maximum 7 µU/mL) [51]. Growth velocity increased from 2.2 to 8.1 cm/year and remained between 5.0 and 8.5 cm/year; at 6 years he measured 89 cm (−5.0 SD) [51]. In the same publication, two siblings from another family from the same locality in Campania, compound heterozygous for the same variant and for R43X (NM_000163.5:c.181C>T p.(Arg61Ter)), had intermittent treatment because of poor adherence; one reached a final height of 110 cm (−9.7 SD) at 23 years [51].

The figures in the open-access article show the index case: the clinical images at 1.7 years and the growth chart with the response to rhIGF-1 (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC8684449/figure/F1/), the velocity curves of the three patients (Figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC8684449/figure/F2/) and the pedigrees with electropherograms (Figure 5, https://pmc.ncbi.nlm.nih.gov/articles/PMC8684449/figure/F5/) [51]. The case shows three practical points: classic GHI may occur without consanguinity; a panel restricted to exonic regions would not have detected the variant; and the maximum dose of mecasermin required intensive glycaemic monitoring, as the labels anticipate [33, 51]. The starting dose used (120 µg/kg twice daily, at 2.1 years) was the maximum label dose and the upper limit of the PES guideline, which suggests preferring 80 µg/kg twice daily, whereas the labels recommend starting with 0.04 mg/kg (EU) or 0.04–0.08 mg/kg (USA) and titrating weekly [31–33].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Without treatment, patients with Laron reach final heights between −5 and −10 SD, that is, 106–142 cm in men and 95–136 cm in women [7, 31]. With mecasermin, the mean adult height gain is about 13 cm relative to that expected, with a cumulative gain of about +1.5 to +2 SD, but most remain below the normal range; early initiation improves the outcome [7, 32, 48, 83]. In STAT5B deficiency, prognosis depends on interstitial lung disease, which caused deaths at 22 and 30 years [2, 17]. In ACLSD and PAPPA2 deficiency, adult height is mildly to moderately reduced, and some patients with ACLSD reach normal height [2, 22]. In IGF-1 resistance, the response to GH is unpredictable, and adult carriers did not show more comorbidities than adults born SGA [35].

Ecuadorian patients with Laron had no deaths from cancer or type 2 diabetes, but longevity is not increased because of high mortality from accidents, alcohol and seizure disorders; raised LDL coexists with normal or better cardiovascular markers [52, 68]. Truncal obesity, hip degeneration in adult women and difficulties of social and occupational integration weigh on adult life [3, 4].

11.2. Surveillance

Table 11.1. Recommended surveillance [2, 28, 31–33, 35, 54, 57, 64]

The sources consulted do not define fixed intervals for most of these tests; the intervals given correspond to the time points that the labels specify [32, 33].

12. Summary and Final Considerations

Growth hormone insensitivity is a class of disorders in which GH is normal or high but IGF-1 is not generated, transported or released, or does not act. Laron syndrome, autosomal recessive due to GHR variants, is the classic form: severe postnatal growth failure, characteristic face, hypoglycaemia, truncal obesity, very low IGF-1, IGFBP-3 and ALS and usually low GHBP. Around it are the dominant-negative forms of GHR and STAT5B, the intronic pseudoexons of GHR, recessive STAT5B deficiency with immunodeficiency and interstitial lung disease, IGF-1 deficiency with IUGR, microcephaly and deafness, acid-labile subunit deficiency with mild short stature and almost undetectable IGFBP-3, PAPPA2 deficiency with high total and low free IGF-1 and IGF-1 resistance due to IGF1R, with IUGR, microcephaly and high IGF-1.

Diagnosis combines auxology, the profile of IGF-1, IGFBP-3, ALS and GHBP and genetic testing by panel with copy number analysis or by exome or genome, bearing in mind that 30–48% of cases have a molecular diagnosis and that deep intronic variants and deletions escape exonic tests. The IGF-1 generation test serves mainly to confirm severe GHI. The SPIGFD criteria differ between the USA and the European Union.

Mecasermin, authorised in the USA since 2005 and in the European Union since 2007, and available in Portugal in the hospital setting, increases growth velocity mainly in the first year and gives a mean gain of about 13 cm in adult height, with better results when started early. The 2016 PES guideline recommends rhIGF-1 in SPIGFD, suggests 80–120 µg/kg twice daily, with a preference for the lower dose, given 20 minutes after a meal, and proposes a prior trial of GH when the cause of IGF-1 deficiency has not been established. Hypoglycaemia, intracranial hypertension, lymphoid hypertrophy and oncological surveillance require family education, administration with meals and cautious titration. In partial forms, somatropin has a variable effect, and rhIGF-1 outside the label criteria has limited data. The Ecuadorian cohort with Laron suggests protection against cancer and diabetes, without increased longevity. Access to diagnosis and treatment remains unequal, and an updated international consensus is lacking.

13. References

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