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case-control·ophthalmology, endocrinology, genetics, pediatric ophthalmology, neuro-ophthalmology·PMC10721018

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

PLOS ONE · 8 authors, 3 centres

AI SUMMARY

FIDELITY 92%

POPULATION16 sporadic patients (13 boys, 3 girls) aged 0.4 to 13.7 years diagnosed with isolated or complex pituitary stalk interruption syndrome (PSIS) based on MRI findings

INTERVENTIONExome sequencing (Agilent SureSelect Human All Exon V4, Illumina HiSeq2000) with analysis of rare/novel variants in genes associated with pituitary development or function

COMPARISONNot applicable (no control group; variants compared to dbSNP138, gnomAD, and in-house database of 1100 exomes)

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This study performed exome sequencing on 16 patients with pituitary stalk interruption syndrome (PSIS) and found pathogenic or likely pathogenic variants in only two cases (12.5%), one with Okur-Chung neurodevelopmental syndrome and one with a novel GLI2 splice site variant. Most identified variants were of uncertain significance, highlighting the low diagnostic yield in isolated PSIS. The findings suggest that isolated PSIS may involve multigenic inheritance or non-coding variants, and that genetic diagnosis remains challenging.

Full summary

3,459 CHARS

**Background:** Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by MRI findings of absent/ectopic posterior pituitary, absent/interrupted pituitary stalk, and anterior pituitary hypoplasia, leading to anterior pituitary deficiencies (e.g., growth hormone deficiency). Pathogenic variants have been reported in genes involved in pituitary development, holoprosencephaly, and other syndromes. Previous exome sequencing of 52 PSIS patients identified pathogenic variants in 39, mostly with complex phenotypes. This study aimed to identify genetic causes in 16 new sporadic PSIS patients.

**Methods:** This retrospective single-center study included 16 patients (13 boys, 3 girls) aged 0.4 to 13.7 years diagnosed with PSIS by MRI (ectopic posterior pituitary in all but three; interrupted/not seen/thin/malformed stalk; anterior pituitary height low in 9, normal in 5, not measured in 2). Growth hormone deficiency was isolated in 10 cases (62.5%) or associated with TSH deficiency (6 cases), ACTH deficiency (1 case), HH (1 case), or multiple deficiencies (2 cases). Additional phenotypes occurred in 6 cases (37.5%), including ophthalmic disorders (4 cases) and Fanconi anemia (2 cases). Exome sequencing was performed using Agilent SureSelect Human All Exon V4 on Illumina HiSeq2000 (average coverage x50). Variants were filtered for novel/rare (MAF<0.01), analyzed with SIFT and Polyphen2, and classified per ACMG guidelines. Karyotyping was normal in all.

**Key Results:** In 13 of 16 patients, variants potentially contributing to the phenotype were identified. Only one patient (case 4) had a pathogenic variant: a heterozygous CSNK2A1 c.A593G:p.K198R missense variant (recurrent in Okur-Chung neurodevelopmental syndrome), presenting with delayed walking (2.4 years), hypotonia, and autism. One patient (case 3) had a likely pathogenic novel splice site variant in GLI2 (c.1368+1G>A), associated with Culler-Jones syndrome/holoprosencephaly 9, presenting with a second anterior pituitary-like structure on MRI. Patient 16 had two PTCH1 variants (p.Y1165C, p.R1291W) and a GLI2 variant (p.V681M), all VUS, with megacisterna magna. Patient 7 carried novel loss-of-function variants in PITX1 and PITX2 (nonsense in PITX2), but only had PSIS and early puberty. Patient 1 had Fanconi anemia with a heterozygous FANCD2 pathogenic variant (p.K261M) plus DNMT1 and RFWD3 VUS. Other VUS included HH genes (FGF17, HS6ST1, KISS1R, CHD7, IL17RD) and holoprosencephaly genes (GLI2, PTCH1). No candidate variants were found in cases 6, 8, and 15. Overall, diagnostic yield was 12.5% (2/16) for pathogenic/likely pathogenic variants.

**Clinical Implications:** This study confirms that genetic diagnosis in isolated PSIS is challenging, with a low yield (12.5%) compared to syndromic forms. Most variants were VUS, suggesting possible multigenic inheritance or non-coding variants. The identification of a CSNK2A1 pathogenic variant highlights that PSIS can be part of a broader neurodevelopmental syndrome. The GLI2 splice site variant supports the role of holoprosencephaly pathway genes in PSIS. Clinically, these findings emphasize the need for comprehensive genetic evaluation in PSIS patients, especially those with additional anomalies, and the importance of considering syndromic causes. The low yield in isolated cases suggests that future research should explore non-coding regions, oligogenic inheritance, and larger cohorts.

PICO

PPOPULATION

16 sporadic patients (13 boys, 3 girls) aged 0.4 to 13.7 years diagnosed with isolated or complex pituitary stalk interruption syndrome (PSIS) based on MRI findings

IINTERVENTION

Exome sequencing (Agilent SureSelect Human All Exon V4, Illumina HiSeq2000) with analysis of rare/novel variants in genes associated with pituitary development or function

OOUTCOME

Identification of pathogenic, likely pathogenic, or variants of uncertain significance (VUS) potentially contributing to PSIS phenotype; diagnostic yield

STUDY TYPE

case-control

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

92% · A

ORIGINAL PAPER

PMC10721018

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

PLOS ONE

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ABSTRACT

Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by an absent or ectopic posterior pituitary, absent or interrupted pituitary stalk and anterior pituitary hypoplasia on magnetic resonance imaging (MRI), as well in some cases a range of heterogeneous somatic anomalies. The triad can be incomplete. Here, we performed exome sequencing on 16 sporadic patients, aged 0.4 to 13.7 years diagnosed with isolated or complex PSIS. Growth hormone deficiency was isolated in 10 cases, or associated with thyrotropin deficiency in 6 others (isolated (2 cases), associated with adrenocorticotropin deficiency (1 case), gonadotropins deficiency (1 case), or multiple deficiencies (2 cases)). Additional phenotypic anomalies were present in six cases (37.5%) including four with ophthalmic disorders. In 13 patients variants were identified that may contribute to the phenotype. However, only a single individual carried a variant classified as pathogenic. This child presented with the typical clinical presentation of Okur-Chung neurodevelopmental syndrome due to a CSNK2A1 missense variant. We also identified variants in the holoprosencephaly associated genes GLI2 and PTCH1 . A likely pathogenic novel splice site variant in the GLI2 gene was observed in a child with PSIS and megacisterna magna. In the remaining 11 cases 26 variants in genes associated with pituitary development or function were identified and were classified of unknown significance. Compared with syndromic forms the diagnostic yield in the isolated forms of PSIS is low. Although we identified rare or novel missense variants in several hypogonadotropic hypogonadism genes (e.g. FGF17 , HS6ST1 , KISS1R , CHD7 , IL17RD ) definitively linking them to the PSIS phenotype is premature. A major challenge remains to identify pathogenic variants in cases with isolated PSIS.

CITATION EXPORT

Raja Brauner, Joelle Bignon-Topalovic, Anu Bashamboo et al.. Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study. PLOS ONE. (2023). https://doi.org/10.1371/journal.pone.0292664

AUTHORS

8 · 3 CENTRES

Raja Brauner, Joelle Bignon-Topalovic, Anu Bashamboo, Ken McElreavey, Nejat Mahdieh, Nejat Mahdieh, Nejat Mahdieh, Nejat Mahdieh

1 Pediatric Endocrinology Unit, Hôpital Fondation Adolphe de Rothschild and Université Paris Cité, Paris, France
2 Human Developmental Genetic Unit, Institut Pasteur, Paris, France
Shaheed Rajaei Hospital: Rajaie Cardiovascular Medical and Research Center, ISLAMIC REPUBLIC OF IRAN

EDITOR / REVIEWER

Nejat Mahdieh