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POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature

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Abstract

Context

POU1F1 mutations are prevalent in Indian CPHD cohorts. Genotype–phenotype correlation is not well-studied.

Aim

To describe phenotypic and genotypic spectrum of POU1F1 mutations in our CPHD cohort and present systematic review as well as genotype–phenotype analysis of all mutation-positive cases reported in world literature.

Methods

Retrospective study of POU1F1 mutation-positive patients from a western-Indian center. PRISMA guidelines based pubmed search of published literature of all mutation-positive patients.

Results

Our cohort had 15 POU1F1 mutation-positive patients (9 index, 6 relatives). All had severe GH, TSH and prolactin deficiencies (GHD, TSHD and PD). TSHD was diagnosed earliest followed by GHD (median ages: TSHD-6 months, GHD-3 years), while PD was more variable. Two sisters had central precocious puberty at 7 years of age. Pubic hair was deficient in all post-pubertal patients (females: P1-P2, males: P3-P4). Splice-site/intronic/frameshift mutations were most common, while missense/nonsense mutations were less frequent (33%). Review of world literature yielded 114 patients (82 index patients) from 58 studies. GHD was present in all patients. TSHD was spared in 12.5% and PD in 4.4% patients. Missense/nonsense mutations accounted for 75% of spectrum. Phenotype-genotype analysis revealed higher mean peak-GH levels (1.1 vs 0.2 ng/ml, p = 0.008) and lower prevalence of anterior-pituitary hypoplasia (63.6% vs 86.3%, p = 0.03) in patients with heterozygous than homozygous and compound heterozygous mutations.

Conclusions

We present largest series of POU1F1 mutation-positive patients. Precocious puberty and defective pubarche are lesser-appreciated phenotypic features. Our mutation spectrum is different from that of world literature. Patients with heterozygous mutations have milder phenotype.

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Authors confirm that data supporting the findings of this study are available within the article.

Abbreviations

CPHD:

Combined Pituitary Hormone Deficiency

POU1F1:

POU class 1 homeobox 1 factor 1

GHD:

Growth Hormone Deficiency

TSHD:

Thyroid stimulating hormone deficiency

PD:

Prolactin deficiency

IGF-1:

Insulin like Growth Factor 1

SDS:

Standard Deviation Score

APH:

Anterior Pituitary Hypoplasia

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Acknowledgement

We sincerely thank Dr Vyankatesh Shivane and Dr Aparna Kamble for their contribution in administrative overview of patient care and data management for this study.

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Author notes

  1. Swati Jadhav and Chakra DiwakerSwati Jadhav and Chakra Diwaker are Joint Authors.

Authors and Affiliations

  1. Department of Endocrinology, Sapthagiri Institute of Medical Sciences and Research Center, Bengaluru, Karnataka, India

    Swati Jadhav

  2. Department of Endocrinology, IndiaSeth G.S. Medical College & KEM Hospital, Parel, Mumbai, Maharashtra, 400012, India

    Chakra Diwaker, Anurag R. Lila, Shantanu Kale, Puja M. Thadani, Sneha Arya, Virendra A. Patil, Nalini S. Shah & Tushar R. Bandgar

  3. Department of Endocrinology, Topiwala National Medical College and BYL Nair Hospital, Mumbai, Maharashtra, India

    Jugal V. Gada

  4. Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Center, Bengaluru, Karnataka, India

    Vijaya Sarathi

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  1. Swati Jadhav
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Correspondence to Anurag R. Lila.

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Jadhav, S., Diwaker, C., Lila, A.R. et al. POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature. Pituitary 24, 657–669 (2021). https://doi.org/10.1007/s11102-021-01140-9

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