Retrospective analysis of the phenotypic and genotypic spectrum of mutation proven POU1F1 patients and to compare them with the published literature.

Introduction:

Combined pituitary hormoneDeficiency (CPHD) is a condition classically characterized by a deficiencyof growth hormone (GH) and at least one other pituitary hormone. The prevalenceof CPHD is estimated to be 1 in 8000 individuals worldwide.1 POU1F1 is one ofthe earliest gene described in 1990 in pathogenesis of CPHDwith  prevalence of 2.8% in CPHD patients with 84 % having nocausative gene found.2 First described in1990 Snell (dw/dw) and Jackson(dwj/dwj) dwarf mice, harboring POU1F1 mutations, presented with greatlyreduced size and hypothyroidism.3 POU1F1 mutation carriers display hypoplasticor normal adenohypophysis with normal pituitary stalk and posterior pituitary.4,5,6

A total of 30 different variants inPOU1F1 have been described, and they are generally recessive with pituitaryhypoplasia and CPHD. Herein, we plan to study our cohort of patients and do asystematic review of the published literature, with the aim of analysingphenotypic and genotypic spectrum of POU1F1 patients worldwide.

Aim:

To study thephenotypic and genotypicspectrum of mutation proven POU1F1 patients in our cohort and to compare themwith the published literature.

Type of study: Retrospective

Methodology:

A retrospective case record analysisof patients diagnosed with Growth Hormone deficiency or Combined PituitaryHormone Deficiency of POU1F1 mutation proven patients (cohort 1)from Jan 2002 -Dec 2019 will be conducted at Endocrine OPD of a tertiary health carecentre.Data will be collected (both baseline and follow up) from medical recordof patients all genetically diagnosed cases of POU1F1.Patient details includingbirth history, age at present, family history of short stature andconsanguinity, anthropometric data (Patient height, patient height SDS, patientweight, patient weight SDS, US:LS Ratio, arm span, mother’s height, mother’sheight SDS, father’s height, father’s height SDS, MPH, MPH SDS), SMR,phenotypic features associated with growth hormone deficiency, biochemicalinvestigations (IGF-1, IGFBP3, T3, T4, FT3, FT4, TSH, 8am cortisol, prolactin,FSH, LH, testosterone), peak GH concentration based on GH stimulation tests(clonidine stimulation test, insulin tolerance test or glucagon stimulationtest), skeletal maturity and MRI findings (anterior pituitary height, locationof posterior pituitary, morphology of pituitary stalk, optic nerves and midlinebrain structures) will be recorded in an approved case record form.Additionally, anthropometric data, SMR, skeletal maturity and biochemicalinvestigations will be documented for follow-up visits. Approximately 20 caserecords will be reviewed for this study. Genetic analysis was offered topatients with Growth Hormone deficiency at the department as a standard ofcare. Some patients have borne the cost of genetic analysis, while some havebeen offered help through donations or trust funds. The genetic testing fromK.E.M is usually out sourced to Medgenome Laboratories.

Cohort 2 would comprise ofsystematic review of published literature (up to Dec 2019) will be done onMEDLINE and Scopus search engines employing following search terms: POU1F1, pit1, CPHD and GHD.

All original and review articlespublished in English were reviewed for inclusion. Only publications describingmutation proven POU1F1 will be included. A secondary search for relevantpublications was carried out by hand searching through the reference lists ofselected publications.

Definitions and Cut offs:

Diagnosis of GHD is based on peak GHconcentration < 7ng/ml in children and <3ng/ml in adults (>18 years)on at-least one GH stimulation test (clonidine stimulation test, insulintolerance test or glucagon stimulation test) with low serum IGF-1 levels.

Hypothyroidism is defined as lowserum free/total T4 with low or inappropriately normal TSH levels.

Hypocortisolism is defined as 8.00am cortisol 5μg/dl and/or serumcortisol < 18 μg/dl at the time of hypoglycaemia during insulin tolerancetest (where available).

Hypogonadism is defined as the clinical absence pubertalonset/progression with low or inappropriately normal serum FSH and LH levels inindividuals with bone age > 13 years in females and >14 years in males.

Hypoplastic pituitary is defined as less than -2 SD of normal whenmaximum height of the pituitary is measured perpendicular to the sella turcica.

Inclusion Criteria:

All patients with growth hormone whovisited the Endocrine OPD from Jan 2002 till Dec 2019.

Exclusion Criteria:

1.      Mutations otherthan POU1F1.

2.      Inadequate data

3.      InsufficientDiagnosis

Statistical analysis:

All categorical variableswill be expressed in actual numbers and percentages. All continuous variableswill be expressed as mean and standard deviation. Categorical parameters willbe compared with chi square test. P value < 0.05 will be considered statisticallysignificant.