Introduction:
Combined pituitary hormone
Deficiency (CPHD) is a condition classically characterized by a deficiency
of growth hormone (GH) and at least one other pituitary hormone. The prevalence
of CPHD is estimated to be 1 in 8000 individuals worldwide.1 POU1F1 is one of
the earliest gene described in 1990 in pathogenesis of CPHD
with prevalence of 2.8% in CPHD patients with 84 % having no
causative gene found.2 First described in1990 Snell (dw/dw) and Jackson
(dwj/dwj) dwarf mice, harboring POU1F1 mutations, presented with greatly
reduced size and hypothyroidism.3 POU1F1 mutation carriers display hypoplastic
or normal adenohypophysis with normal pituitary stalk and posterior pituitary.
4,5,6
A total of 30 different variants in
POU1F1 have been described, and they are generally recessive with pituitary
hypoplasia and CPHD. Herein, we plan to study our cohort of patients and do a
systematic review of the published literature, with the aim of analysing
phenotypic and genotypic spectrum of POU1F1 patients worldwide.
Aim:
To study thephenotypic and genotypic
spectrum of mutation proven POU1F1 patients in our cohort and to compare them
with the published literature.
Type of study: Retrospective
Methodology:
A retrospective case record analysis
of patients diagnosed with Growth Hormone deficiency or Combined Pituitary
Hormone Deficiency of POU1F1 mutation proven patients (cohort 1)from Jan 2002 -
Dec 2019 will be conducted at Endocrine OPD of a tertiary health care
centre.Data will be collected (both baseline and follow up) from medical record
of patients all genetically diagnosed cases of POU1F1.Patient details including
birth history, age at present, family history of short stature and
consanguinity, anthropometric data (Patient height, patient height SDS, patient
weight, patient weight SDS, US:LS Ratio, arm span, mother’s height, mother’s
height SDS, father’s height, father’s height SDS, MPH, MPH SDS), SMR,
phenotypic features associated with growth hormone deficiency, biochemical
investigations (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 stimulation
test), skeletal maturity and MRI findings (anterior pituitary height, location
of posterior pituitary, morphology of pituitary stalk, optic nerves and midline
brain structures) will be recorded in an approved case record form.
Additionally, anthropometric data, SMR, skeletal maturity and biochemical
investigations will be documented for follow-up visits. Approximately 20 case
records will be reviewed for this study. Genetic analysis was offered to
patients with Growth Hormone deficiency at the department as a standard of
care. Some patients have borne the cost of genetic analysis, while some have
been offered help through donations or trust funds. The genetic testing from
K.E.M is usually out sourced to Medgenome Laboratories.
Cohort 2 would comprise of
systematic review of published literature (up to Dec 2019) will be done on
MEDLINE and Scopus search engines employing following search terms: POU1F1, pit
1, CPHD and GHD.
All original and review articles
published in English were reviewed for inclusion. Only publications describing
mutation proven POU1F1 will be included. A secondary search for relevant
publications was carried out by hand searching through the reference lists of
selected publications.
Definitions and Cut offs:
Diagnosis of GHD is based on peak GH
concentration < 7ng/ml in children and <3ng/ml in adults (>18 years)
on at-least one GH stimulation test (clonidine stimulation test, insulin
tolerance test or glucagon stimulation test) with low serum IGF-1 levels.
Hypothyroidism is defined as low
serum free/total T4 with low or inappropriately normal TSH levels.
Hypocortisolism is defined as 8.00am cortisol 5μg/dl and/or serum
cortisol < 18 μg/dl at the time of hypoglycaemia during insulin tolerance
test (where available).
Hypogonadism is defined as the clinical absence pubertal
onset/progression with low or inappropriately normal serum FSH and LH levels in
individuals with bone age > 13 years in females and >14 years in males.
Hypoplastic pituitary is defined as less than -2 SD of normal when
maximum height of the pituitary is measured perpendicular to the sella turcica.
Inclusion Criteria:
All patients with growth hormone who
visited the Endocrine OPD from Jan 2002 till Dec 2019.
Exclusion Criteria:
1. Mutations other
than POU1F1.
2. Inadequate data
3. Insufficient
Diagnosis
Statistical analysis:
All categorical variables
will be expressed in actual numbers and percentages. All continuous variables
will be expressed as mean and standard deviation. Categorical parameters will
be compared with chi square test. P value < 0.05 will be considered statistically
significant.
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