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Genetic spectrum and predictors of mutations in four known genes in Asian Indian patients with growth hormone deficiency and orthotopic posterior pituitary: an emphasis on regional genetic diversity

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Abstract

Context

Regional variation in prevalence of genetic mutations in growth hormone deficiency (GHD) is known.

Aim

Study phenotype and prevalence of mutations in GH1, GHRHR, POU1F1, PROP1 genes in GHD cohort.

Methods

One hundred and two patients {Isolated GHD (IGHD): 79; combined pituitary hormone deficiency (CPHD): 23} with orthotopic posterior pituitary were included. Auxologic, hormonal and radiological details were studied. All four genes were analysed in IGHD patients. POU1F1 and PROP1 were studied in CPHD patients.

Results

Of 102, 19.6% were familial cases. Height SDS, mean (SD) was − 5.14 (1.63). Peak GH, median (range) was 0.47 ng/ml (0–6.59), 72.5% patients had anterior pituitary hypoplasia (APH). Twenty mutations (novel: 11) were found in 43.1% patients (n = 44, IGHD-36, CPHD-8). GHRHR mutations (n = 32, p.Glu72* = 24) were more common than GH1 mutations (n = 4) in IGHD cohort. POU1F1 mutations (n = 6) were more common than PROP1 mutations (n = 2) in CPHD cohort. With few exceptions, this prevalence pattern is contrary to most studies in world-literature. No patients with peak GH > 4 ng/ml had mutations, signifying it as negative predictor. While many parameters were significant on univariate analysis, only positive family history and lower median peak GH levels were significant predictors of mutations on multivariate analysis in IGHD patients.

Conclusion

At variance with world literature, we found reverse predominance of GHRHR over GH1 mutations, POU1F1 over PROP1 mutations and predominance of GHRHR p.Glu72* mutations thus re-affirming the regional diversity in GHD genetics. We report positive and negative predictors of mutations in GHD.

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Abbreviations

GHD:

Growth hormone deficiency

IGHD:

Isolated growth hormone deficiency

CPHD:

Combined pituitary hormone deficiency

GH1:

Growth hormone 1

GHRHR:

Growth hormone releasing hormone receptor

PROP1:

PROP paired-like homeobox 1

POU1F1:

POU class 1 homeobox 1

EPP:

Ectopic posterior pituitary

PSIS:

Pituitary stalk interruption syndrome

IGF-1:

Insulin like growth factor 1

SDS:

Standard deviation score

GH:

Growth hormone

TSH:

Thyroid stimulating hormone

FSH:

Follicle stimulating hormone

LH:

Luteinizing hormone

ACTH:

Adrenocorticotropic hormone

TRH:

Thyrotropin releasing hormone

BLAST:

Basic local alignment search tool

ExAC:

Exome aggregation consortium

APH:

Anterior pituitary hypoplasia

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Funding

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Author information

Author notes

  1. Shantanu Kale and Jugal V. Gada are Joint Authors.

Authors and Affiliations

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

    Shantanu Kale, Swati Jadhav, Anurag R. Lila, Sweta Budyal, Hiren Patt, Puja M. Thadani, Sneha Arya, Aparna A. Kamble, Virendra A. Patil, Shilpa Sankhe, Vyankatesh Shivane, Vijaya Raghavan, Tushar R. Bandgar & Nalini S. Shah

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

    Jugal V. Gada

  3. Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Center, Bangalore, Karnataka, India

    Vijaya Sarathi

  4. Department of Medicine, J N Medical College, Belgaum, Karnataka, India

    Manjunath R. Goroshi

  5. Department of Endocrinology, K S Hegde Medical Academy, Mangalore, Karnataka, India

    Shrikrishna Acharya

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  1. Shantanu Kale
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Corresponding author

Correspondence to Virendra A. Patil.

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The authors declare that they have no conflict of interest.

Ethical approval

The study has been approved by the Institutional Ethics Committee II, Seth GS medical college and KEM hospital, Mumbai, India.

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All the patients/their parents have given written informed consent for participation in the study.

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Kale, S., Gada, J.V., Jadhav, S. et al. Genetic spectrum and predictors of mutations in four known genes in Asian Indian patients with growth hormone deficiency and orthotopic posterior pituitary: an emphasis on regional genetic diversity. Pituitary 23, 701–715 (2020). https://doi.org/10.1007/s11102-020-01078-4

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