Clinical trial NCT05334563: Incidence of cCPHD in Denmark - a National Observational Study
Official title: The Incidence of Congenital Combined Pituitary Hormone Deficiency in Denmark - a National Observational Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Combined Pituitary Hormone Deficiency Genetic Form
Combined Pituitary Hormone Deficiency
Keywords: Combined pituitary hormone deficiency
Congenital combined pituitary hormone deficiency
Congenital multiple pituitary hormone deficiency
Incidence of pituitary hormone deficiency
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Aalborg University Hospital
name: Aarhus University Hospital
First posted: 2022-04-19
Enrollment: 127
Sex: ALL
Minimum age (years): 1
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study aims to include all congenital combined pituitary hormone deficiency patients in Denmark born between January 1, 1996, and December 31, 2020, identified through the ICD-10 diagnosis code searches in the Danish National Patient Registry and locally at the four highly specialized hospitals.

Brief summary: The pituitary gland is a small pea-sized gland that produces a variety of important hormones. Some children are born with a deficient production of two or more pituitary hormones. This rare and potentially severe disease is called congenital combined pituitary hormone deficiency (cCPHD).

cCPHD can cause many different symptoms, some of which appear shortly after birth and others later in childhood. Symptoms that appear shortly after birth are e.g., development of very low blood sugar, disturbances in the salt balance, and severe dehydration, whereas symptoms that appear later in life are short stature, missing pubertal development, fatigue, and sensitiveness to cold. Fortunately, it is possible to replace the missing hormones.

Currently, it is unknown how common cCPHD is. Therefore, the investigators wish to examine 1) how many children are diagnosed with cCPHD before the age of 18 years, 2) how many children are diagnosed with cCPHD at age \<1 year, 1-8 years, 9-17 years, and 3) the patients' hormone deficiency characteristics and brain MRI scans.

The investigators will identify the patients by searching for diagnosis codes used for pituitary disease and pituitary malformations in the Danish National Patient Registry and locally at the four hospitals approved for the treatment of cCPHD in children. Through the searches, the investigators expect to identify approximately 1500 patients. The investigators will then review the hospital files of all identified patients to exclude patients with only one hormone deficiency and patients with an acquired cause of the disease. The investigators aim to include all cCPHD patients in Denmark born in the period 1996 and 2020.

Detailed description: 1. Background

   Congenital combined pituitary hormone deficiency (cCPHD) is defined as the partial or complete loss of more than one hormone secreted from the pituitary gland, caused by genetic or prenatal factors. Combined pituitary hormone deficiency (CPHD) is a broader term covering both congenital and acquired forms.

   The incidence and prevalence of cCPHD are not known.

   Pituitary hormone deficiencies most commonly occur in the adenohypophysis involving growth hormone (GH), thyroid-stimulating hormone (TSH), corticotropin (ACTH), prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). More rarely, the neurohypophysis is also affected, resulting in vasopressin deficiency.

   Symptoms and clinical features of cCPHD are variable, even within the same family, including the extent and severity of the hormone deficiencies, the age of clinical onset and the cerebral comorbidity. Moreover, delay inadequate treatment may affect the clinical outcome and prognosis.

   Newborns with clinical overt cCPHD may present in the first days of life with hypoglycemia, electrolyte abnormalities, hypothermia, conjugated hyperbilirubinemia, poor appetite, vomiting, and failure to thrive. In boys, gonadotropin deficiency may present with hypogonadism including micropenis. Patients with vasopressin deficiency may have central diabetes insipidus from birth with polyuria and quickly develop severe hypernatremic dehydration.

   Delayed onset of cCHPD may occur as a gradual process, usually with growth hormone deficiency (GHD) as the first manifestation, followed by TSH deficiency and later other hormone deficiencies including FSH/LH deficiency.

   MRI of the brain and the pituitary region commonly, but not always, reveal anatomical abnormalities including aplasia or hypoplasia of the adenohypophysis and/or pituitary stalk. Aplasia, hypoplasia, or ectopic position of the neurohypophysis may be seen. Associated brain abnormalities may include septo-optic dysplasia (SOD) and aplasia/hypoplasia of other brain structures, especially in the midline. Syndromes, including cCPHD with other brain or organ abnormalities, include heterotaxy syndrome, Worster-Drought Syndrome, congenital proprotein convertase 1/3 deficiency, FOXA2 mutation syndrome and many others.

   Genetic testing can be helpful to understand the diverse phenotypic picture of cCPHD.

   The development of the pituitary gland is dependent on the sequential temporal and spatial expression of transcription factors and signaling molecules and occurs in a well-defined sequence of events. Some of these factors include HESX1, LHX3, LHX4, POU1F1, PROP1, SIX6, OTX2, PITX2, GLI2, and SOX3, all of which have been shown to play a role in the development and maturation of the pituitary gland.

   Disruption of this cascade due to mutations in any of these gene products affects the ontogeny of one or several of the pituitary cell types and ultimately leads to hormone deficiency with or without extra-pituitary abnormalities. Previous studies have shown a higher prevalence of genetic mutations in familial cases, where both dominant, recessive and X-linked inheritance has been demonstrated. Still, most patients with cCPHD have remained genetically unexplained.

   The treatment of cCPHD consists of the substitution of the deficient pituitary hormones or their target hormones, including growth hormone, thyroid hormone, sex hormones, glucocorticoids, and vasopressin. Eventual other cerebral or other organ syndromal manifestations must be identified and managed.
2. Materials and methods

   This study is a national study based on ICD10 diagnosis codes from The Danish National Patient Registry (DNPR) and the four tertiary hospitals: Odense Universitetshospital, Aarhus Universitetshospital, Rigshospitalet, and Aalborg Universitetshospital. The DNPR contains a unique registration of all hospitalized patients in the country since 1977; with WHO ICD10 diagnosis codes since 1994. The registry identifies patients based on the unique personal identification number of each person living in Denmark. The diagnosis code searches at the four tertiary hospitals are made in addition to the DNPR search to provide a higher probability of identifying all patients with cCPHD in Denmark.

   The DNPR and the four local hospital searches will be performed using the ICD10 codes E23.0-E23.9 (pituitary hormone deficiencies and other diseases in the pituitary gland), Q89.2G (congenital malformation of the pituitary), and Q04.0-Q04.9 (other congenital brain malformations) for the 25-year period: 1st of January 1996 - 31st of December 2020. Patients with the additional diagnoses C69.0-C72.9 (cancer in eyes, brain, other parts of the CNS), C75.1-C75.3 (cancer in the pituitary, corpus pinealis and craniopharyngeomas), D35.2 - D35.4 (benign tumours of the pituitary gland, corpus pineale, or ductus craniopharyngei) and D33.0-D33.9 (benign tumours in the brain and spinal cord) will be excluded. Patients with the ICD10 diagnosis codes A80.0-A89.9 (central nervous system infections) and/ or I60.0-I64.9 (nontraumatic subarachnoid hemorrhage, nontraumatic intracerebral hemorrhage, other and unspecified nontraumatic intracranial hemorrhage, cerebral infarction, stroke not specified as haemorrhage or infarction) registered before the time of the E23.0-E23.9 diagnosis will also be excluded.

   For the identified patients a retrospective hospital file review will be performed to confirm the cCPHD diagnosis and to exclude patients who meet one of the exclusion criteria.

   The data used in this project are found in patient journals and include the following: birthdate, sex as indicated by the presence of male/female genitals (male/female), born in Denmark (yes/no), presence of ICD-10 diagnosis codes of interest (yes/no), date and results of blood samples and stimulation tests of interest (low/normal/inadequately high/high), date and result of urine osmolality measurement (low/normal/high), abnormalities of the adenohypophysis, neurohypophysis, pituitary stalk, midline and cerebrum by the latest MRI (aplasia/hypoplasia/ectopic/normal or yes/no), and hospital file descriptions of clinical features of hormone deficiencies (yes/no).

   All hormone deficiencies will be retrospectively validated using a set of hormone deficiency criteria. The criteria were defined by five experienced pediatric endocrinologists, including a representative from each of the highly specialized hospitals, and were based on national and international endocrinological guidelines, published literature, and the clinical practice at the highly specialized hospitals.
3. Ethics

   This study was approved by the Management Secretariat and the Regional Secretariat and Law of The Region of Southern Denmark (j.no. 20/58158). To ensure compliance with The General Data Protection Regulation and The Danish Data Protection Act, data were collected and managed in collaboration with Open Patient data Explorative Network (OPEN) using Microsoft SharePoint and REDCap (Research Electronic Data Capture).
4. Participatory design

   The study protocol is designed after preliminary contacts with 10 parents to children with cCPHD at Odense University Hospital. The parents expressed a need of dissemination of several aspects of cCPHD to improve future management of this rare disease. Some stressed the need of identification of early signs of cCPHD to contribute to fastest possible diagnosis, as diagnosis delay has been a major, sometimes life-threatening problem for their children, e.g. severe hypernatriemic dehydration with a s-sodium of 180 mmol/L in a neonate with cCPHD and diabetes insipidus. Others stressed the benefits of dissemination of good results of early and centralized expert treatment including androgen therapy in infant boys with hypogonadism. Others wanted to pass on a message that children with non-syndromic cCPHD can live a normal life with normal school performance. Others stressed that CPHD should be looked for in syndromes with potential CPHD or children with an unknown syndrome to optimize e.g. their growth and cerebral function. One parent has agreed to be a part of the project group.
5. Perspectives

   Given that cCPHD is a rare and complex, potentially life-threatening disease, the paucity of literature on the subject and the lack of estimates of incidence, this study is expected to provide important information to be published. A good understanding of the illness is crucial and may lead to patients getting diagnosed earlier.
6. Dissemination of the results

   The study will be published as one or two papers in peer-reviewed international journals. A Danish and English press release will be made at the time of publication. Oral presentation(s) or poster(s) will be presented at national meetings, e.g. The Danish Society of Paediatric Endocrinology (DSPE) and international meetings, e.g. the annual European Society of Paediatrics (ESPE) meeting or ENDO. A popular talk is scheduled at a meeting in patient organization The Danish Pituitary Network
7. Project group

   Henrik Thybo Christesen, Consultant, Professor, ph.d, MD, Hans Christian Andersen Children's Hospital, Odense University Hospital, Denmark. Project supervisor.

   Dorte Hansen, Consultant, Associate Professor, ph.d, MD, Hans Christian Andersen Children's Hospital, Odense University Hospital, Denmark. Project co-supervisor.

   Niels Holtum Birkebæk, Consultant, ph.d, MD, Dept. of Pediatrics, Aarhus University Hospital Skejby, Denmark. Study site collaborator.

   Ann-Margrethe Rønholt Christensen, Associate professor, Dept. of Pediatrics, Aalborg University Hospital, Denmark. Study site collaborator.

   Rikke Bodin Beck-Jensen, Consultant, ph.d, MD, Dept. Of Growth and Reproduction, Rigshospitalet. Study site collaborator

   Louise Kjersgaard Jakobsen, research year medical student
8. Fonds

This work was supported by Odense University Hospital Fund (j.no. A4599), and Dagmar Marshalls Fund (29/04/2021).

Eligibility criteria: Inclusion Criteria:

* Born between January 1, 1996, and December 31, 2020.
* Registered in Danish National Patient Registry or locally at Hans Christian Andersen Children´s Hospital, Odense University Hospital, Department of Growth and Reproduction, Rigshospitalet, Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital or Department of Pediatrics, Aalborg University Hospital with an ICD-10 diagnosis code E23·0-E23·9 (hypofunction and other disorders of pituitary) and/or Q89·2G (congenital malformation of pituitary) before age 15 years.
* Validated secondary/tertiary deficiency of two pituitary hormones before age 18 years.

Exclusion Criteria:

* ICD-10 diagnosis codes indicating acquired PHD.
* No available hospital files.
* Less than two documented secondary/tertiary hormone deficiencies.
* Acquired CPHD.

Primary outcomes:
measure: The incidence of congenital combined pituitary hormone deficiency in Denmark diagnosed before age 18 years.
timeFrame: 1996 to 2020
Secondary outcomes:
measure: The incidence of congenital combined pituitary hormone deficiency in Denmark diagnosed at age <1 year, 1-8 years, and 9-17 years.
timeFrame: 1996 to 2020
measure: Hormone deficiency characteristics and brain MRI abnormalities in the congenital combined pituitary hormone deficiency patients
timeFrame: 1996 to 2020
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: HCA Research, Odense University Hospital
Study officials:
affiliation: Hans Christian Andersen Children´s Hospital, Odense University Hospital
name: Henrik T Christesen, ph.d.
role: PRINCIPAL_INVESTIGATOR
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