Diagnosis of Pituitary Stalk Interruption Syndrome in a Newborn Presenting With Recurrent Hypoglycemia: A Rare Case Report

Introduction: Isolated growth hormone deficiency (IGHD) involves multiple genes, yet characterization of its mutational landscape and genotype-phenotype correlations remains limited. The aim of this study was to analyze a large cohort of patients with genetic IGHD and describe associated genotypes and phenotypes. Methods: Descriptive study of IGHD patients with an identified genetic cause was referred for targeted NGS panel analysis through the GENHYPOPIT network between 2017 and 2024, and complementary targeted family analysis. Results: Among 205 patients with IGHD, 23 (11.2%) had a pathogenic (P) or likely pathogenic (LP) variant. The average age at diagnosis was 3.9 years, and 47% of patients had pituitary hypoplasia. Seventy percent of variants were in GH secretion genes, 39% in GH1, mostly with autosomal dominant transmission, 13% in GHRHR, and 18% in GHSR, with autosomal dominant or recessive inheritance and incomplete penetrance. Variants in genes involved in pituitary development were rarer (30% of variants). The most commonly affected pituitary development gene was GLI2 (13%). GLI2 variants were always associated with pituitary stalk interruption syndrome. The remaining variants were in POU1F1 (9%), HESX1 (4%), and SOX3 (4%). We report 10 new P or LP variants. Family analyses (n = 30) broadened the genotype-phenotype correlation, identified de novo variants, as well as the first ever reported case of GH1 mosaicism. Conclusion: Our study broadens the spectrum of genetic variations associated with IGHD. In most cases, the implicated gene is involved in GH secretion, but our results highlight that IGHD can also be caused by genes involved in pituitary development. These findings confirm the importance of genetic analysis in IGHD, to improve patient management and genetic counselling.

Association between serum prolactin and anterior pituitary dysfunction in pituitary stalk interruption syndrome: a retrospective study of 155 patients from a large tertiary medical center in China

A case report of pituitary stalk interruption syndrome presenting with upper gastrointestinal bleeding

You Don’t Look a Day Over 16: A Case of Pituitary Stalk Interruption Syndrome Diagnosed in Adulthood

Patients diagnosed with pituitary stalk interruption syndrome (PSIS) exhibit heterogeneous endocrinological and radiological presentations. The aim of this study was to assess the correlation between MRI features in children with PSIS and their pituitary hormonal profile, and answer the question whether pituitary MRI can serve as a prognostic factor of pituitary insufficiency. The study included 50 children diagnosed with PSIS. Hormonal data were collected at the first and most recent visits; with a median follow-up of 5.9 years. Data collected before 2016 were retrospective; thereafter, prospective. At initial diagnosis, 32 patients (64%) presented with isolated pituitary hormone deficiencies. During follow-up, 15 of them (47%) developed additional deficits, increasing the prevalence of combined pituitary hormone deficiency (CPHD) from 16 (32%) to 31 patients (62%). In the remaining 17 patients (34%), only the initial isolated growth hormone deficiency (GHD) diagnosis persisted. Progression to CPHD occurred in 87.5% of patients with stalk agenesis compared to 33.3% with stalk hypoplasia (p = 0.013). All cases of arginine vasopressin deficiency (AVPD) were observed exclusively in patients with the absence of the posterior pituitary (Fisher's exact test, p < 0.000001; odds ratio = 0, with 95% CI: 0-0.04). Furthermore, the presence of optic nerve hypoplasia (ONH) was strongly associated with the development of CPHD. Children with PSIS require repeated reassessment of pituitary function if CPHD is not present at the initial evaluation, as progression to complete pituitary insufficiency may occur over time. The absence of the pituitary stalk may serve as a sensitive marker of CPHD, whereas the absence of the posterior pituitary appears to predispose patients to AVPD. Additionally, the coexistence of ONH and PSIS may be associated with greater severity of anterior pituitary hormonal dysfunction. Patients who do not develop CPHD typically present with growth failure as the main manifestation, along with pituitary stalk hypoplasia and partial GHD.

Pituitary Stalk Interruption Syndrome (PSIS) is a rare congenital anomaly characterised by an interrupted or thin pituitary stalk, hypoplasia of the anterior pituitary and an absent or Ectopic Posterior Pituitary (EPP). Clinically, this condition manifests as pituitary gland dysfunction, which may include Growth Hormone Deficiency (GHD), global pituitary insufficiency and developmental delay. Early diagnosis is crucial, as delayed recognition can result in suboptimal growth outcomes. Magnetic Resonance Imaging (MRI) of the brain plays a pivotal role in identifying pituitary gland abnormalities associated with PSIS. The present case series describes five patients (3 males, 2 females) and highlights the importance of brain MRI in diagnosing PSIS, emphasising the significance of early intervention to optimise patient outcomes. Early diagnosis and initiation of hormone replacement therapy are essential in improving clinical outcomes.

Background: Congenital pituitary stalk interruption syndrome (PSIS) is a developmental disorder of the hypothalamo–pituitary axis defined radiologically by an absent or markedly thinned pituitary stalk, ectopic or absent posterior pituitary bright spot, and a hypoplastic anterior pituitary. In pediatrics, PSIS is a leading “organic” substrate for severe growth hormone deficiency (GHD) and a frequent cause of evolving multiple pituitary hormone deficiencies (MPHD/CPHD), yet clinical recognition is often delayed because initial manifestations vary by age and sex. Objectives: (1) To summarize the anatomical hallmarks and radiological associations of PSIS in children/adolescents and their relationship to endocrine severity. (2) To synthesize the impact of PSIS on linear growth and the GH–IGF-1 axis, including response patterns to recombinant human GH (rhGH). (3) To outline a pragmatic, anatomy-informed management and surveillance approach for pediatric PSIS. Methods: A narrative structured review of PubMed/Scopus-indexed pediatric literature (January 2001–December 2025) was performed using terms related to “pituitary stalk interruption,” “ectopic posterior pituitary,” “hypopituitarism,” “child*,” and “adolescent*.” We prioritized cohort studies with MRI-phenotype correlation and GH outcomes, and contemporary expert reviews/guidelines for replacement therapy. Extracted data included presentation triggers, frequency of pituitary deficits, auxology/IGF-1 characteristics, MRI patterns (complete vs partial PSIS), extra-pituitary malformations, and management implications. Results: Across major pediatric cohorts, GHD is highly prevalent and commonly severe; central hypothyroidism, ACTH deficiency, and hypogonadotropic hypogonadism occur with variable frequencies, and deficiencies may progress over time (2–5). MRI severity—particularly non-visualization of the stalk and a smaller anterior pituitary—correlates with greater endocrine burden and earlier presentation (4,5). Manifestations range from early infancy signs (hypoglycemia, micropenis/cryptorchidism) to later childhood short stature. IGF-1 is frequently low at diagnosis, and rhGH typically induces robust first-year catch-up growth, with response modulated by age at start and baseline severity (2,7,8). PSIS frequently coexists with midline/extra-pituitary anomalies in subsets, reinforcing a developmental field defect model (2,6). Conclusions: Pediatric PSIS is an MRI-defined congenital disorder with wide clinical expression but predictable anatomy–endocrine correlations. Early MRI recognition, complete baseline pituitary profiling, and longitudinal re-screening for evolving deficiencies are central to preventing morbidity. Growth outcomes are generally favorable when rhGH is initiated early and combined with timely replacement of other deficient axes.

No abstract available

Pituitary stalk interruption syndrome, an uncommon cause of growth hormone deficiency and hypopituitarism, is often revealed during the neonatal period and in childhood.

To analyze the clinical and genetic characteristics of a Chinese pedigree affected with congenital Isolated growth hormone deficiency (IGHD). A pedigree presenting with Pituitary stalk interruption syndrome (PSIS) (including the proband, his two younger sisters and both parents) who had visited the Capital Institute of Pediatrics Affiliated to Capital Medical University in September 2020 was selected as the study subject. Clinical data were collected. Peripheral blood samples were collected from the proband and his family members. Following the extraction of genomic DNA, whole-exome sequencing (WES) was carried out, and candidate variants were validated by Sanger sequencing. The pathogenicity of the candidate variants was classified based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Institute Pediatrics of Capital Medical University (Ethics No.: SHERLL2025033). The proband and one younger sister (Ⅱ3) presented with growth retardation, short stature, and a doll-like facies. Another younger sister (Ⅱ2) and both parents had normal heights and appearance. Sanger sequencing confirmed that the proband and his younger sister (Ⅱ3) both harbored compound heterozygous variants of the GHRHR gene, namely c.776C>A (p.T259K) and c.1166G>A (p.R389Q). The other younger sister (Ⅱ2) and the parents were heterozygous carriers. The c.1166G>A (p.R389Q) variant was unreported previously. Based on the guidelines from the ACMG, it was classified as variant of uncertain significance (PM2_Supporting+BP4). Bioinformatics analysis indicated a deleterious effect on the protein function. Variants of the GHRHR gene probably underlay the pathogenesis of IGHD in this pedigree. Above finding has provided a basis for the clinical diagnosis and genetic counseling for this family.

Abstract Disclosure: T. Handa: None. R. Soohey: None. M. Gortakowski: None. Introduction: Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary disorder characterized by MRI findings a thin or interrupted pituitary stalk, ectopic posterior pituitary tissue, and hypoplasia or aplasia of the anterior pituitary. PSIS commonly presents with combined pituitary hormone deficiencies at a variable age of onset. Presentation: A female infant with an uncomplicated prenatal course born at 39 5/7 weeks was admitted to the NICU for apnea and desaturation with concern for seizure after admission. Initial point of care glucose was less than 20mg/dL. MRI/MRA ruled out venous sinus thrombosis and hypoxic-ischemic encephalopathy (HIE) but did not comment on pituitary abnormalities. Critical sample at 6 hours of life (HOL) showed serum glucose 38 mg/dL (50-80 mg/dL), insulin 2.9 uU/mL (2.6-24.9), beta-hydroxybutyrate less than 0.05 mmol/L (0.27-5.0), and cortisol 0.9 mcg/dL. Given lab values, MRI was requested to be re-read with attention to the pituitary. A hyperintense focus at the inferior margin of the pituitary infundibulum compatible with an ectopic posterior pituitary was found, consistent with PSIS. Hypoglycemia was treated with IV Dextrose up to a glucose infusion rate of 10mg/kg/min, and the infant was weaned off dextrose-containing fluids by DOL 14. On DOL 4, an ACTH stimulation test was consistent with central adrenal insufficiency (CAI) (baseline cortisol 0.6 mcg/dL, ACTH 3.3 pg/mL (7.2-63.3) and cortisol 60 minutes 5.9 mcg/dl). Stress-dose hydrocortisone was started and infant transitioned to maintenance with clinical improvement. Levothyroxine was further started for Serial low-normal free T4 values for age with normal TSH, suggestive of central hypothyroidism (CeH). At outpatient follow up at approximately 6 weeks of age, IGF-1 was 12 ng/mL (17-185), and IGFBP-3 was 351 mcg/L (1053-3271). Infant was subsequently started on somatotropin therapy for growth hormone deficiency (GHD). Discussion: This case highlights the variable presentation of PSIS. PSIS is a rare diagnosis in the neonatal period, with prevalence rates not well documented. In this patient, an MRI was obtained to evaluate for HIE however revealed findings consistent PSIS. Further, given an inappropriate elevation of insulin in the setting of hypoglycemia this was suggestive of transient stress hyperinsulinism. CAI and CeH were identified and treated in the NICU and GH therapy was started in the outpatient setting for GHD. This case emphasizes the importance of evaluating for combined hormone deficiencies in patients with PSIS. Conclusion: We present a unique case of PSIS diagnosed during the initial evaluation for concern for HIE. This case illustrates the diagnostic role of MRI and a complete biochemical evaluation for affected axes. Treatment of PSIS involves hormone supplementation tailored to the patient’s clinical picture. Presentation: Sunday, July 13, 2025

Disclosure: M.E. Patterson: None. L. Meller: None. G. Akkad: None.Background: Panhypopituitarism, characterized by multiple pituitary hormone deficiencies, is generally diagnosed in infancy or early childhood. Panhypopituitarism is less commonly initially diagnosed in older children and teenagers. Herein, we present a unique case of a 12-year-old female with late-onset panhypopituitarism presenting with short stature and concomitant bilateral distal arthrogryposis, who was successfully treated with growth hormone (GH) without worsening of arthrogryposis contractures. Case Description A 12-year-old female born at 38 weeks of gestation with a past medical history of arthrogryposis presented for an endocrinology evaluation due to short stature. She was projected to be at the 75th percentile on the growth curve but had been in the 10th-25th percentile for most of her childhood but had only recently dropped below the 5th percentile by age 12. She was found to have Tanner stage 1 breast development and Tanner stage 1 pubic hair. Contractures were noted in both hands. Work up from the primary care physician confirmed normal karyotype (46,XX). She was found to have concurrent GH deficiency (IGF-1: 12 ng/mL, Z-Score -4.6 SD), hypothyroidism (Free T4: 0.56 ng/dL), and adrenal insufficiency (baseline cortisol 2.8 ug/dL). Cortisol and growth hormone stimulation testing confirmed their deficiencies. Given her panhypopituitarism, an MRI was completed and showed findings compatible with pituitary stalk interruption syndrome (PSIS). Treatment began with hydrocortisone (9 mg/m^2/day) and levothyroxine (37.5 mcg daily) with normalization of thyroid hormone levels. GH replacement was eventually started after careful discussions with the family out of concerns that it might exacerbate her hand arthrogryposis contractures. She was started on weekly subcutaneous Skytrofa injections (7.6 mg SQ weekly, 0.24 mg/kg/week). At her three-month follow-up visit, her growth velocity had increased to 8.7 cm/year. By the next three-month follow-up visit, her growth velocity recorded at 17.4 cm/year. A repeat bone age X-ray taken was consistent with her chronological age, and her predicted adult height had increased to 64 inches, compared to the previous prediction of 60 inches. All without any worsening of hand contractures. Conclusion: Currently, no reports exist on the effects of GH therapy on arthrogryposis contractures. However, clinicians may remain hesitant given concerns of GH therapy on mediating skeletal growth and worsening arthropathies. This case report highlights that initiation of GH therapy may lead to a significant growth improvement without aggravating arthrogryposis-related contractures. However, generalizations should be made with caution, and we emphasize the importance of shared-decision making and frequent follow up in the use of GH therapy in patients with congenital contractures.Presentation: Saturday, July 12, 2025

The majority of congenital hypopituitarism (CH) cases remain genetically unexplained. The transmembrane receptor Roundabout-1 (ROBO1), activated through interaction with SLIT-family proteins, plays crucial role in axonal guidance, branching, targeting, and midline axonal crossing. ROBO1 variants have been associated with pituitary stalk interruption syndrome and highly variable pituitary-phenotypes, ranging from isolated growth hormone deficiency (IGHD) to combined pituitary hormone deficiency (CPHD). This study aimed to investigate the genetic basis of CH in a newborn and to review current evidence linking ROBO1 variants withCH. We report the presence of two ROBO1variants in compound heterozygosity, the NM_002941:c.2914G>A, p.(Ala972Thr) and the novel NM_002941:c.3757G>A, p.(Val1253Met), as well as the identification of the novel NOTCH3 variant NM_000435:c.1505C>T, p.(Ser502Phe) and the novel GPR161 variant NM_001375883.1:c.1117C>T, p.(His373Tyr), in a newborn with CPHD, dysmorphic features and midline abnormalities. This case, together with accumulating evidence, supports ROBO1 as a potential causative gene for CH. ROBO1 should be considered during genetic evaluation of patients with CH and midline abnormalities. The co-occurrence of NOTCH3 and GPR161 variants raises the possibility of an oligogenic or multigenic etiology. The cross-talk between ROBO/SLIT and NOTCH signaling pathways may contribute to the complex phenotype observed and warrants further functional investigation.

Delayed Presentation of Pituitary Stalk Interruption Syndrome (PSIS)

Abstract Background Pituitary stalk interruption syndrome (PSIS) is a rare congenital malformation of the pituitary stalk that leads to hypopituitarism, presenting with a variety of endocrine dysfunctions, including delayed puberty, short stature, and hypothyroidism. Magnetic resonance imaging (MRI) typically reveals a thin or absent pituitary stalk, hypoplasia of the anterior pituitary, and ectopic posterior pituitary. This case aims to highlight the importance of early recognition and multidisciplinary management to improve long-term outcomes in patients with PSIS. Case presentation We present a 21-year-old male with delayed puberty and multiple endocrine abnormalities, including hypothyroidism, hypogonadism, and cortisol insufficiency. The patient exhibited physical features such as a depressed nasal bridge, macroglossia, and a short, wide neck. MRI revealed a hypoplastic anterior pituitary, absent pituitary stalk, and an ectopic posterior pituitary. Laboratory findings included elevated TSH, prolactin, and low levels of free T4, testosterone, and cortisol. Treatment with levothyroxine, prednisolone, and chorionic gonadotropin was initiated. After 3 months, laboratory values improved, although hormone levels remained abnormal. Conclusions This case highlights the importance of early detection and appropriate treatment for PSIS. MRI is a crucial diagnostic tool for patients presenting with hypopituitarism. A multidisciplinary approach to managing PSIS, including lifelong monitoring and tailored interventions, is essential for optimizing patient outcomes and addressing both endocrine and developmental concerns.

ObjectiveTo evaluate the baseline and follow-up clinical and radiological characteristics of a paediatric cohort initially diagnosed with isolated congenital growth hormone deficiency (IGHD) and pituitary morphology abnormality in MRI.Patients and methodsObservational, ambispective and longitudinal review of paediatric patients with an initial diagnosis of growth hormone deficiency with pituitary morphology abnormality in MRI followed-up in a single tertiary hospital.ResultsAfter mean 11.3 (± 3.5DS) years of follow-up, the thirty patients (20 males) were classified into two groups: (1) isolated congenital growth hormone deficiency (IGHD) with 24 patients (9.5 years median follow up), and (2) combined pituitary hormone deficiencies (CPHD) with 6 patients (13.5 years median follow up). Median age at diagnosis was IGHD 3.0 [2.0–4.0] and CPHD 3.0 [1.5–5.2] years. Regarding the cerebral MRI scan results, 2 patients had septo-optic dysplasia (CPHD), 5 had pituitary stalk interruption syndrome (3 IGHD), one had ectopic posterior pituitary (IGHD), 16 had anterior pituitary hypoplasia (15 IGHD) and 6 had the latter two conditions combined (5 IGHD). In genetic studies, 1 of 25 patients had positive NGS panel results and it was in the IGHD group. The target gene detected was GLI2. Clinical exome sequencing was performed with six patients, yielding inconclusive results (1 in the IGHD group and 5 in the CPHD group). Array CGH was performed with eight patients (4 in the IGHD group and 4 in the CPHD group) and was negative in all patients. In the CPHD group, associated deficiencies begin to appear after 5 years [4.0–6.0] median follow-up, with thyrotropin being the most frequent (80%), followed by gonadotropin deficiency. ACTH and AVP deficiencies were less frequent.ConclusionsMultiple hormone deficiencies were diagnosed during this cohort’s follow-up evaluation, whose first presentation was isolated growth hormone deficiency and pituitary morphology abnormality in MRI. Pathogenic gene variant involved in congenital hypopituitarism (GLI2) was found in one patient. Regular follow up of pituitary hormonal function in such patients is advisable due to the risk of new added deficiencies.

INTRODUCTIONPituitary stalk interruption syndrome (PSIS) is a rare congenital condition characterized by either isolated or combined pituitary hormone deficiency. This paper presents 6 cases of pituitary stalk interruption syndrome diagnosed and managed in a tertiary Pediatric Endocrinology Center. CASEAnalytical review of the medical records of patients followed up in Putrajaya Hospital, Malaysia from year 2017–2024 revealed 6 male patients with confirmed diagnosis of PSIS. Among the cohort, 50% of them had significant perinatal events including severe neonatal jaundice, prolonged non-invasive ventilation support, sepsis or hypoxic events. A total of 17% were delivered via emergency caesarean section and the rest were born via unremarkable spontaneous vaginal delivery. Clinical presentation varied with 50% of patients presenting at birth with ambiguity of genitalia, another 50% of patients presented in adolescents with short stature and delayed puberty. Features of soft dysmorphism were observed in 67% of them. All patients have growth hormone deficiency, with 83% of them having additional pituitary hormone deficiency. Half of them have multiple pituitary hormone deficiencies. None of the patients in the cohort had clinical manifestations of diabetes insipidus. MRI imaging revealed absence of pituitary stalk on all patients. All patients who have been treated with growth hormone therapy showed improvement in height velocity with a mean of 10 (± 2.5) cm per year. CONCLUSIONChildren with PSIS often have a very broad spectrum of clinical and biochemical presentations. Screening and evaluation of the pituitary-hypothalamic hormone axis is critical to guide management. This clinical entity often presents with growth retardation and thus early diagnosis is critical to allow for timely management of these patients with growth hormone therapy.

Pituitary Stalk Interruption Syndrome (PSIS) is a rare congenital disorder characterized by a triad of anatomical anomalies affecting the pituitary gland. We present the case of a 21-year-old male with congenital hypopituitarism. MRI findings were critical in confirming PSIS and guiding further management. This case highlights the essential role of imaging in evaluating patients with endocrine dysfunction and growth failure.

Bilateral femoral head necrosis in early adulthood with pituitary stalk interruption syndrome: need for comprehensive medical education on the impact of growth retardation in misdiagnosis