8-Year Safety and Efficacy of Long-Acting GH Therapy in Pediatric IGHD II with Chiari Malformation Type 1: A Case Report with Review of Literature

Introduction

Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency in children, occurring 1 in 4000–10,000 live births.¹ While most cases are idiopathic, up to 30% are familial and require genetic subclassification.² IGHD can be divided into autosomal recessive (Type IA and IB), X-linked (Type III), and autosomal dominant (Type II) forms.³ IGHD type II (IGHD II) is characteristically caused by heterozygous GH1 mutations on chromosome 17q23, leading to aberrant splicing and dominant-negative effects.⁴ This subtype accounts for 11–38% of familial IGHD cases and 3–11% of all IGHD.⁵

Daily recombinant human GH (rhGH) has long been the standard treatment, but long-acting growth hormone (LAGH) formulations, administered weekly, have emerged as a promising alternative to improve adherence and quality of life.⁵ Although Phase III trials demonstrated their non-inferiority to rhGH, long-term real-world data on its efficacy and safety in pediatric IGHD remain limited.^5–7 Therefore, further observational studies and extended follow-up are needed to fully characterize the long-term benefits and potential risks of these newer formulations. Another clinical challenge is the coexistence of IGHD with Chiari malformation type 1 (CM1), defined by herniation of the cerebellar tonsils into the spinal canal, which has been reported in some pediatric IGHD patients.⁸ CM1 is of particular concern during GH therapy because changes in intracranial pressure or cerebrospinal fluid dynamics—whether related to growth acceleration, fluid shifts, or rare GH-related effects—could theoretically exacerbate tonsillar herniation or precipitate symptomatic progression (headaches, syringomyelia, or neurologic deficits). This potential risk underscores the need for careful neurologic assessment and imaging surveillance when initiating or monitoring GH treatment in patients with known CM1. To date, however, long-term outcomes of LAGH in genetically confirmed IGHD II complicated by CM1 have not been described. Here, we report an over eight-year follow-up of such a case, providing insights into treatment efficacy and safety in this complex clinical setting.

Case Presentation

This study was approved by the Ethics Committee of Shenzhen Children’s Hospital (Approval Number: 202503302). The research was conducted in accordance with ethical principles such as the Declaration of Helsinki, and the patient and his guardian provided informed consent.

Clinical History

A 4-year 3-month-old boy presented in April 2017 with progressive growth failure. Despite normal birth parameters, linear growth was markedly impaired from infancy, with heights of 63 cm, 70 cm, and 75 cm at ages 1, 2, and 3 years, respectively. Parents reported poor appetite, frequent nocturnal awakenings, and hyperactivity. Family history was unremarkable, and the mid-parental height was 173.5 cm. The patient had previously received traditional herbal therapies for short stature without benefit.

Physical Examination

At baseline, the patient measured 80.2 cm in height (–6.43 SDS) and 10.0 kg in weight, with a body mass index of 15.6 kg/m² (10th–25th percentile). Body proportions were preserved (sitting height/height ratio 0.59; arm span/height ratio 0.97). Craniofacial assessment showed normocephaly, intact midline structures, and no dysmorphic features such as frontal bossing, midfacial hypoplasia, or clefting. Dermatologic examination revealed no neurocutaneous stigmata. Musculoskeletal evaluation showed normal joint mobility without ligamentous laxity, with symmetrically small hands and feet. Neurological examination was normal, with normal tone, strength, and no focal deficits. Pubertal status was prepubertal (bilateral testicular volume 1 mL, stretched penile length 3 cm, and absence of pubic/axillary hair), consistent with chronological age.

Auxiliary Examinations

Metabolic and General Biochemistry

The results of complete blood count, routine urine, blood glucose, lipid, liver and kidney function, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), neuron-specific enolase (NSE), human chorionic gonadotropin (HCG), and thyroid function analyses were normal. Vitamin D status was sufficient.

Growth Axis

Baseline GH was 0.23 ng/mL, with undetectable IGF-1 (<25 ng/mL). A standardized GH stimulation test (intravenous arginine 0.5 g/kg plus oral levodopa 0.01 g/kg) showed complete non-responsiveness (peak GH 0.23 ng/mL at all timepoints [0–120 min]), confirming severe GHD. The flat response pattern and undetectable IGF-1 supported a primary hypothalamic-pituitary defect.

Gonadal and Adrenal Axes

Adrenal function testing demonstrated preserved hypothalamic-pituitary-adrenal axis integrity, with 8:00 AM cortisol of 8.36 μg/dL (reference: 5–25 μg/dL) and ACTH 8.05 pg/mL (reference: 10–60 pg/mL). Steroid intermediates, including 17α-hydroxyprogesterone (0.06 ng/mL) and DHEA-S (3.20 μg/dL), were within prepubertal range. Gonadal assessment revealed prepubertal patterns: LH 0.85 mIU/mL, FSH 0.74 mIU/mL, testosterone <0.1 nmol/L, and estradiol <20 pg/mL. Prolactin levels were normal (11.94 ng/mL; reference: 4–23 ng/mL). Collectively, these findings confirmed isolated GH deficiency without evidence of additional pituitary hormone deficiency.

Imaging Findings

Skeletal maturation assessed by left hand/wrist radiography was markedly delayed, with a bone age of 2 years at chronological age 4.2 years (−2.2 SD below population norms) (Figure 1). Contrast-enhanced pituitary MRI demonstrated severe hypoplasia (height 1 mm) with a partial empty sella, consistent with structural pituitary maldevelopment. Additionally, cerebellar tonsillar descent of 4 mm below the foramen magnum confirmed CM1 (Figure 2). Spinal radiography showed no vertebral anomalies.

Figure 1 Left hand and wrist radiograph at age 4.2 years, corresponding to a bone age of 2 years.

Figure 2 Midline sagittal T1-weighted MRI of the brain at diagnosis (age 4.2 years).

Genetic Analysis

Whole-exome sequencing revealed a heterozygous GH1 splice-site variant (NM_000515.5:c.291+1G>A, rs71640277) at the invariant +1 position of intron 3. Bidirectional Sanger sequencing confirmed its de novo origin, demonstrating heterozygosity in the proband (NP1600940) and wild-type sequences in both parents (VP1601842/VP1601843) (Figure 3). According to ACMG/AMP guidelines, the variant was classified as pathogenic, fulfilling five key criteria: (1) PVS1, as the variant alters the canonical splice donor site of a gene where loss-of-function is a known disease mechanism; (2) PS2, supported by confirmed de novo occurrence in this familial context; (3) PM1, given its location at a highly conserved splice donor region; (4) PP3, with concordant in silico predictions (SpliceAI score 0.99, MaxEntScan 8.9→0.4) indicating near-certain splicing disruption; and (5) PP4, based on perfect phenotypic correlation with severe IGHD type II (peak stimulated GH 0.23 ng/mL, undetectable IGF-1 <25 ng/mL, and pituitary hypoplasia). This variant’s clinical significance is further reinforced by its established association with aberrant GH1 splicing in multiple independent reports and the characteristic pituitary structural abnormalities observed in our patient. This variant has been previously classified as pathogenic (PVS1+PM1+PP3+PP4 by ACMG criteria) and associated with severe IGHD type II.⁹

Figure 3 Sanger Sequencing Confirmation of Heterozygous c.291+1G>A Mutation in the GH1 Gene in the Proband and Wild-Type Alleles in Both Parents. Forward sequencing traces are shown for the proband (NP1600940), father (VP1601842), and mother (VP1601843). The red arrow indicates the heterozygous c.291+1G>A mutation (NM_000515.5) in the proband, which presents as overlapping G and A peaks (indicated by the arrow). Both parents show wild-type sequences (single G peak) at the same position, confirming the de novo origin of this variant.

Diagnostic Confirmation

The patient met definitive criteria for IGHD II based on: (1) profound growth failure (−6.43 height SDS) with proportionate short stature and delayed bone age; (2) biochemical evidence of complete GH deficiency with preserved function of other pituitary axes; and (3) identification of a pathogenic GH1 splice-site variant (c.291+1G>A) fulfilling ACMG criteria. Pituitary MRI findings of hypoplasia (height 1 mm) and concomitant Chiari I malformation provided structural corroboration of this congenital disorder.

Treatment and Follow-Up

Treatment Initiation and Clinical Follow-Up

This patient was enrolled in a Phase IV observational, prospective, post-trial study (NCT03290235).¹⁰ The patient initiated weekly LAGH (Jintrolong, GeneScience Pharmaceuticals Co., Ltd., Changchun, China) at age 4.2 years with a starting dose of 0.12 mg/kg/week, titrated to 0.20 mg/kg/week based on growth response. Within the first treatment year, he exhibited marked catch-up growth with a height velocity of 16.6 cm/year (+2.75 SDS change), achieving −3.68 height SDS from a baseline of −6.43 SDS, while bone age advanced 1.5 years. This accelerated growth trajectory continued through mid-childhood, reaching −2.75 SDS by year 3 (annualized ΔSDS +1.2/year). Pubertal onset occurred at 11.2 years (testicular volume 4 mL) with maintained growth potential, culminating in a height of 147.8 cm (−0.72 SDS) at 12.2 years, accompanied by appropriate bone age progression (12.4 years). The eight-year follow-up illustrates the sustained efficacy and safety of individualized LAGH therapy in severe IGHD II, even with concomitant pituitary hypoplasia and CM1 (Table 1). A longitudinal growth curve (Figure 4) depicts the patient’s consistent catch-up growth trajectory from age 4 to 13 following initiation of LAGH.

Table 1 Chronological Clinical and Anthropometric Data

Figure 4 Growth chart of the patient from age 4.2 to 12.2 years under long-acting GH therapy. The graph illustrates significant catch-up growth during the first year and sustained height gain thereafter, demonstrating long-term therapeutic efficacy. Note: The form is based on data from the 2005 Physical Development Survey of children in nine cities of China.

During follow-up, concerns regarding the patient’s academic performance prompted a neurocognitive evaluation. The Wechsler Intelligence Scale for Children – Fourth Edition (WISC-IV, Chinese Simplified, Short Form) was conducted at the age of 12, revealing a Verbal Comprehension Index of 52, a Perceptual Reasoning Index of 76, and a Full-Scale IQ of 55, indicating significant cognitive impairment.

Biochemical Response

Serial biochemical monitoring consistently demonstrated IGF-1 levels within the therapeutic target (61–267 ng/mL, never exceeding +2 SDS) and stable IGFBP-3 concentrations (3.8–4.6 mg/L). Regular monitoring of blood and urine parameters, calcium and phosphorus metabolism, glucose, lipids, and hepatic and renal functions consistently showed normal ranges. These findings confirmed the favorable long-term metabolic safety profile of LAGH administration.

Imaging Follow-Up

Longitudinal imaging was performed to assess skeletal maturation, pituitary morphology, and spinal integrity. Bone age progression (Table 1) demonstrated a steady catch-up toward chronological age, correlating with linear growth improvement. Pituitary MRI (baseline 2017 vs. follow-up 2023, Figure 5) revealed no progression of the incidental CM1. Serial spinal radiographs (2017–2023, Figure 6) showed no evidence of secondary scoliosis a known comorbidity in CM1 and no progression of cerebellar tonsillar descent progression.

Figure 5 Paired pituitary MRIs (2017 and 2023) illustrating stable gland hypoplasia and intact posterior pituitary bright spot. Repeat imaging was justified solely to evaluate CM1 stability, given debates about routine MRI in isolated GHD.

Figure 6 Serial spinal radiographs (2017–2023) confirming absence of scoliosis and static CM1 anatomy.

Adverse Events and Tolerability

The patient remained adherent to weekly LAGH therapy during the entire follow-up. No serious adverse events or LAGH-related complications—such as injection-site reactions, intracranial hypertension, glucose intolerance, neoplastic events, or progression of scoliosis—were observed during the entire 8-year monitoring period.

Discussion

LAGH therapies were developed to reduce injection burden and improve adherence compared with daily rhGH. The earliest LAGH approvals date back to the late 2010s, yet long-term safety and efficacy data remain limited, especially in rare diseases. This study presents the first reported 8-year follow-up of LAGH therapy in a pediatric patient with genetically confirmed IGHD II complicated by CM1. Over the treatment course, the patient’s height improved markedly from −6.43 SDS to −0.72 SDS. Comprehensive biochemical and imaging follow-ups revealed no significant adverse effects, demonstrating both the long-term efficacy and safety of LAGH in this rare and complex clinical scenario.

Several recent case series describe the coexistence of Chiari I malformation (CIM/CM1) and idiopathic growth hormone deficiency (GHD) in pediatric patients and report outcomes after initiation of recombinant human growth hormone (rhGH) therapy.¹¹ Five cases describe children (ages 5–10 years) who presented for evaluation of short stature and were found on MRI to have CIM in addition to idiopathic GHD. The majority were asymptomatic for CIM at presentation; diagnoses were established during endocrine workup for growth failure. Two patients had prior posterior fossa decompression for symptomatic CIM before endocrine treatment, while others remained asymptomatic throughout follow-up. All five patients were treated with rhGH (daily or weekly regimens), demonstrated good height responses over the available follow-up intervals, and—except for the few published adverse reports described below—did not show clinical or radiological progression of CIM while on therapy.

Research presents mixed findings regarding effects of rhGH on CIM. A minority of earlier case reports described symptomatic worsening or new findings after GH initiation—including increased tonsillar descent, syringomyelia, and central sleep apnea—prompting neurosurgical intervention in some cases.^8,12–14 Proposed mechanisms for deterioration include GH/IGF-1–mediated increases in cerebrospinal fluid (CSF) production leading to raised intracranial pressure and differential somatic versus cranial growth producing traction at the craniocervical junction.⁸ Conversely, several more recent cohorts and case series have not observed meaningful radiological progression attributable to GH therapy; some reports even described radiologic improvement after treatment.^12,15 These heterogeneous findings have led to recommendations for individualized, multidisciplinary care and careful longitudinal monitoring rather than categorical avoidance of GH.

From Genotype to Phenotype

This case illustrates a rare and complex presentation of IGHD II caused by a de novo GH1 intron 3 splice site mutation (c.291+1G>A) co-occurring with CM1. This variant, located at a canonical splice donor site, has been confirmed as pathogenic. Mutations affecting splice sites in GH1, particularly those involving exon 3, lead to aberrant mRNA splicing.⁹ The resulting exon 3 skipping produces a truncated 17.5-kDa GH isoform, which not only lacks biological activity but also exerts a dominant-negative effect on secretion of the normal 22-kDa GH isoform.¹⁶ Its retention in the endoplasmic reticulum, disruption of Golgi function, and interference with protein trafficking contribute to severe GHD.

The patient’s early onset and severe phenotype, characterized by profound short stature (−6.43 SDS) and extremely low peak GH (0.23 ng/mL) at diagnosis, is highly consistent with the deleterious effects of GH1 splice site mutations.¹⁷ The presence of a dominant-negative protein implies that even if some endogenous GH is produced, its function is compromised, necessitating robust exogenous GH replacement. This clear genotype–phenotype concordance underscores the prognostic importance of early genetic testing, particularly in infants with severe short stature (< −3 SDS), to enable timely and individualized intervention.

Long-Term Safety of LAGH Therapy

Overall, LAGH therapy demonstrated a sustained safety profile over eight years, with no evidence of neurological deterioration or CM1 progression, underscoring its safe use even in complex cases involving Chiari I malformation when coupled with vigilant monitoring.

The co-occurrence of pituitary hypoplasia and suspected CM1 on initial MRI added clinical complexity. Pituitary abnormalities, including hypoplasia, are common in IGHD II. Moreover, CM1 has been reported in up to 20% of children with GHD, suggesting a possible shared developmental anomaly involving both the central nervous and endocrine systems.¹⁸ While the GH1 mutation represented the primary genetic etiology of the patient’s GHD, the presence of CM1 warranted careful neurological monitoring alongside endocrine management.

Earlier reports raised safety concerns: two GH-treated children developed worsening tonsillar descent and syringomyelia, necessitating surgical decompression,¹³ and a 2022 systematic review similarly advised cautious monitoring due to potential exacerbation in asymptomatic cases. However, more recent larger cohorts have shown reassuring findings. A 2024 cohort of 34 pediatric GH-treated patients reported no new intracranial hypertension or CM-I progression. Additionally, individual case studies have documented objective radiological improvements in syringomyelia and CM-I following GH therapy.¹⁹

In our study, the stability of CM1 over eight years, without progression or neurological symptoms, is a favorable outcome. These findings underscore the importance of comprehensive imaging beyond the pituitary in GHD patients, especially those with genetic etiologies or unusual presentations. They further highlight the need for a multidisciplinary approach involving pediatric endocrinologists and neurosurgeons to ensure holistic care and monitor both growth and neurological status.

Long-Term Efficacy of LAGH Therapy

Effective management of GHD requires both early initiation and sustained adherence. LAGH therapy has emerged as a promising alternative to daily injections, with the potential to improve compliance and clinical outcomes. Data from the Italian ECOS cohort (n = 73 naïve GHD children) demonstrated that mean adherence with daily GH remained > 85% over 3 years, yielding a mean height SDS gain of +0.41 in year 1.²⁰ However, the adherence to daily GH generally declines over time, often dropping below 80% by the second year. By contrast, weekly LAGH regimens have shown adherence rates reaching 97.5% at 12 months, significantly outperforming daily dosing cycles (mean 91.8%) in device-based studies.²¹ In Turner syndrome and other pediatric endocrine disorders, early and frequent injections correlate with lower compliance, reinforcing the potential advantage of weekly formulations for young patients. While limited, evidence from meta-analyses and registry data support the switch to LAGH improving adherence and satisfaction without compromising efficacy or safety.²²

Our patient, initiated on LAGH at age 4.2, achieved rapid catch-up growth (–6.43 to –3.68 SDS in the first year, Δ+2.75 SDS/year), with a height of –0.72 SDS after 8 years. This trajectory exceeded normative gains reported in daily GH cohorts (≈ +0.4 SDS in year 1 with ≥85% adherence). Additionally, sustained growth velocity of 6 cm/year in years 7–8 outperformed typical long-term daily GH outcomes (3–4 cm/year). However, growth velocity plateaued near –1 SDS during puberty (Δ+0.15 SDS/year despite escalation to 0.20 mg/kg/week), consistent with the attenuated pubertal response seen in IGHD II.²³ Comparative data from the LG Growth Study (4-year Δ+1.8 SDS with LAGH¹³ highlight this case’s exceptional trajectory, though the pubertal plateau underscores the need for dynamic dosing protocols in severe GHD. Strategies such as timely pubertal dose adjustments or supplementation or earlier prepubertal dose escalation merit consideration.

Among pediatric GHD populations, most LAGH studies report up to 4–5 years of continuous treatment, with the LG Growth Study showing 4-year follow-up in 193 weekly LAGH–treated children,²⁴ and real-world PEG-rhGH data extending to 5 years with durable growth outcomes.²⁵ Extension studies of somatrogon and somapacitan have also confirmed long-term efficacy and safety through 5 years.²⁶ To our knowledge, no previous report has documented weekly LAGH therapy extending to 8 years in a genetically confirmed IGHD II patient, especially with coexisting Chiari I malformation, highlighting its novelty and clinical significance.

This case addresses a key gap identified by recent consensus statements, which highlight the scarcity of real-world, long-term LAGH data.¹⁸ By demonstrating sustained efficacy, safety, and high adherence, it provides rare evidence that LAGH can deliver durable benefits in routine practice, supporting its broader adoption for pediatric patients with severe GHD requiring prolonged therapy.

Lessons from the Present Case

Pediatric neuroimaging studies in children with GHD have demonstrated that higher IGF-1 levels are correlated with increased integrity of key brain structures specifically the corpus callosum and thalamus and improved cognitive functions, including working memory and processing speed.²⁷ GH1 mutations have also been reported to potentially affect cognitive development in children.²⁸ Early GH initiation, ideally before age 2, has been associated with improved neurocognitive and motor outcomes in pediatric GHD. In prepubertal short children, two years of GH therapy significantly increased IQ scores. Weekly LAGH further improves compliance in young patients and may maximize these benefits.¹⁹ In our patient, therapy began at age 4.2, and neurocognitive assessment at age 12 revealed impairment. Given evidence that early intervention improves cerebral development and IQ, it is plausible that initiation at age 1–2 may have yielded even greater neurodevelopmental gains. This case prompts reflection on the possibility that earlier detection and treatment might contribute to improved intellectual outcomes, emphasizing the need for timely diagnosis and intervention. However, because this is a single observational case, neurocognitive outcomes cannot be causally attributed to the timing of GH therapy. Multiple factors—including the underlying GH1 mutation, the presence of Chiari I malformation, environmental influences, and other comorbidities—could have contributed to the cognitive profile observed. Thus, while the case supports the rationale for early detection and intervention, definitive conclusions about causality require larger, controlled studies with long-term neurodevelopmental follow-up.

Cost, Access, Immunogenicity, and Ethical/Practical Concerns

While LAGH and early genetic testing offer potential clinical advantages, these benefits must be weighed against several important concerns. First, LAGH formulations are often substantially more expensive than daily rhGH, which may limit access, increase out-of-pocket costs for families, and create inequities across healthcare systems. Second, many LAGH platforms have limited long-term exposure data: although trials and extensions report safety through 3–5 years for some products, potential late or rare adverse events are incompletely characterized and demand ongoing post-marketing surveillance and registry data. Third, immunogenicity is a theoretical and practical concern for modified GH molecules or carrier-conjugated platforms; anti-drug antibodies—while infrequent in most published series—could reduce efficacy or produce immune-mediated effects, so monitoring antibody responses during long-term use is advisable. Fourth, targeted early genetic testing in infants with severe phenotypes can be clinically useful, but broader policies for early GH screening or routine genetic testing raise ethical and practical challenges: risks include overdiagnosis, false positives, psychosocial labeling, the complexities of informed proxy consent and incidental findings, variable laboratory and counseling capacity, and the potential diversion of resources from higher-yield interventions.

Limitations

Important limitations of this report include its single-case design, lack of a comparator group, potential confounding from genotype, coexisting CM1, and environmental factors, limited adherence measurement methods, and the possibility of reporting bias. These limitations constrain generalizability and preclude causal inference; our findings should therefore be regarded as hypothesis-generating and indicative of the need for larger, controlled, long-term studies and registries.

Conclusion

This is the first and longest reported real-world follow-up of weekly LAGH in a genetically confirmed IGHD II patient with CM1, supporting its safety and efficacy. The patient’s cognitive impairment prompts reflection on the possibility that earlier detection and treatment might contribute to improved intellectual outcomes.