OPEN Research Support

Medical student, pregraduate research year student
Louise Kjersgaard Jakobsen
H. C. Andersen Children's Hospital, Odense University Hospital

Projekt styring
Projekt status    Open
Data indsamlingsdatoer
Start 01.03.2021  
Slut 31.01.2022  

Congenital Combined Pituitary Hormone Deficiency in Denmark

Short summary

Some children are born with a pituitary gland that has an insufficient production of two or more hormones (cCPHD). This is a rare, but very severe illness. The incidence and prevalence of the illness is not known, and the symptoms and clinical features are very variable. Because of the severity of the illness, fast and adequate treatment is very important and may affect the clinical outcome and prognosis.

This study aims to 1) estimate the national prevalence and incidence of cCPHD 2) To describe the variable clinical presentation of cCPHD in a national cohort and to compare the clinical presentation it to possible congenital abnormalities in the brain and pituitary gland seen on MRI scan.


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.

The incidence of hypopituitarism in general is reported to be 12-42 per million inhabitants per year; prevalence 300-455 per million inhabitants, but this probably represents underestimate. The incidence and prevalence of cCPHD is 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 in adequate 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 hypernatriemic 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 and ACTH 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. Today however most patients with congenital GHD or cCPHD have remained genetically unexplained.

Although the incidence of reported mutations in cCPHD patients is low, current research continues to delineate the complexities of pituitary development and more clearly define the molecular basis of hormone deficiency in these patients.

The treatment of cCPHD consists of 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.


The aims of this study are

A1) To estimate the national prevalence and incidence of cCPHD in children and adolescents in Denmark.

A2) To describe the variable clinical presentation of cCPHD in a national cohort and to compare the clinical presentation it to possible congenital abnormalities in the brain and pituitary gland seen on MRI scan.

Description of the cohort

This study aims to include all patients with congenital combined pituitary hormone deficiency in Denmark diagnosed in the 25-year period 1996-2020. The search will be restricted to only include children under the age of 15 years at the time of diagnosis.

Data and biological material

Data in part A1:

The Region of Southern Denmark has approved access the following data in the patient's journals:

- Results of following endocrinological blood samples: adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolaktin, cortisol, triiodthyronin (T3), thyroxin (T4), frit thyroixin (frit T4), insulin-like growth factor 1 binding protein 3 (IGF1-BP3), østradiol, testosteron.

- Date and age at time the blood samples mentioned above was collected

- Results of following endocrinological tests: Synacthentest, GH-stimulationstest og GnRH-stimulationstest.

- Date and age at the time the tests mentioned above were conducted

- ICD-10 E23.0-E23.9 diagnoses: Date and age of the time of diagnosis

- ICD-10 Q04.0-Q04.9 diagnoses: Date and age of the time of diagnosis

- Information about the presence of ICD-10 diagnosis code A80.0-A89.9. If present: date and age at the time of registration.

- Information about the presence of ICD-10 diagnosis code I60.0-I64.9. If present: date and age at the time of registration.

- Written description of MRI-cerebrum scans, CT-cerebrum scans and ultrasound of cerebrum scans.

- Date and age at the time of the scans.

- Pituitary hormone substitution treatment: number of hormone substitutions treatments

Data in part A2:

Upon informed consent, for each patient finally included the data seen below will be extracted from the hospital files:

Diagnostic imaging: MRI of brain and pituitary Family history: Family history of cerebral or pituitary disease

Parents: Parental age, parental height, previous pregnancies and number of siblings.

Pregnancy: spontaneous or assisted fertilization, medications, infections, exposures and complications.

Birth: Single/multiple birth, sex, gestational age, birth weight (SD), birth length (SD), head circumference (SD), Apgar score and complications.

Syndrome: Syndromic clinical and paraclinical features (cerebral, incl. vision, hearing, language, epilepsy, cerebral palsy and others), syndromic diagnoses, age at first recognized syndromic feature, age at diagnosis, diagnostic tests and treatment for syndromic features.

Growth data: age, length/height (SD), weight (SD), BMI (SD)), bone age by X-ray, Tanner stage of puberty and occurrence of death. Predicted adult height (if estimated). Education, occupation and school performance (if stated) and the result of neurological examination.

Genetic analyses: genetic test results (only 2-6 genes with importance for the development of the pituitary gland will be investigated).

cCPHD diagnosis: Age at first symptoms of cCPHD, age at each pituitary hormone deficinecy (sequential onset), age at diagnosis of cCPHD, number of pituitary hormone deficiencies, hormone replacement therapy (age at onset, side effects, dose, discontinuation), diagnostic test results.

Organizational: Referral from/to other hospitals, number of diagnostic tests, number of X-rays and MRIs (eventual other imaging), number of admissions, number of outpatient clinic contacts and transition to adult clinic.

Collaborating researchers and departments

Dept. of Pediatrics, Aarhus University Hospital

  • Niels Holtum Birkebæk - Consultant, ph.d, MD

Dept. of Pediatrics, Aalborg University Hospital

  • Ann-Margrethe Rønholt Christensen - Associate professor, MD

Dept. of Growth and Reproduction, Rigshospitalet

  • Rikke Bodin Beck-Jensen - Consultant, ph.d, MD

Hans Christian Andersen Children's Hospital

  • Dorte Hansen - Consultant, Associate Professor, ph.d, MD

Dept. of Clinical Genetics, Odense University Hospital

  • Klaus Brusgaard - ph.d, MSc