Diagnosis and Incidence of Congenital Combined Pituitary Hormone Deficiency in Denmark-A National Observational Study

Abstract

Context: Congenital combined pituitary hormone deficiency (cCPHD) is the loss of ≥2 pituitary hormones caused by congenital factors.

Objective: We aimed to estimate the national incidence of cCPHD diagnosed before age 18 years and in subgroups.

Methods: Patients with cCPHD were identified in the Danish National Patient Registry and Danish hospital registries in the period 1996-2020. Hospital files were reviewed and incidences calculated using background population data. Incidence was the main outcome measure.

Results: We identified 128 patients with cCPHD; 88 (68.8%) were males. The median (range) age at diagnosis was 6.2 (0.01-19.0) years. The median (25th;75th percentile) number of hormone deficiencies at diagnosis was 3 (3; 4) at <1 year vs 2 (2; 2) at 1-17 years, P < .0001. Abnormal pituitary magnetic resonance imaging findings were seen in 70.3% (83/118). For those born in Denmark aged <18 years at diagnosis (n = 116/128) the estimated national incidence (95% CI) of cCPHD was 10.34 (7.79-13.72) per 100 000 births, with an annual incidence rate of 5.74 (4.33-7.62) per million. In subgroup analysis (diagnosis <1 vs 1-17 years), the incidence was highest in the 1-17 years subgroup, 7.97 (5.77-11.00) vs 1.98 (1.39-2.84) per 100 000 births, whereas the annual incidence rate was highest at <1 year, 19.8 (13.9-28.4) vs 4.69 (3.39-6.47) per million births.

Conclusion: cCPHD had the highest incidence rate and the most hormone deficiencies in those diagnosed at <1 year. The incidence was highest in the 1-17 years age group, underscoring the need for multiple pituitary hormone investigations throughout childhood and adolescence in children with only 1 hormone deficiency.

Trial registration: ClinicalTrials.gov NCT05334563.

Keywords: cCPHD; cMPHD; congenital combined pituitary hormone deficiency; congenital hypopituitarism; diagnosis of hypopituitarism; incidence.

Figure 1.

Flow chart of the identification of the national congenital combined pituitary hormone deficiency (cCPHD) cohort and the national cCPHD incidence cohort. Patients at risk of cCPHD were identified through searches on ICD-10 diagnosis codes E23.0-E23.9 (hypofunction and other disorders of pituitary), Q89.2G (congenital malformation of pituitary), and Q04.0-Q04.9 (other congenital malformations of brain). All potential cCPHD cases were examined through retrospective hospital file reviews to validate the cCPHD diagnosis from uniform criteria. DNPR, Danish National Registry; CPHD, combined pituitary hormone deficiency. ^aC69.0-C72.9; n = 69, C75.1-C75.3; n = 4, D33.0-D33.9; n = 53, D35.2-D35.4; n = 41, A80.0-A89.9; n = 8, I60.0-I64.9; n = 4. ^bInfections/autoimmunity; n = 1, brain neoplasm and treatment hereof; n = 8, leukemia/lymphoma and treatment hereof; n = 2, severe eating disorder; n = 1, birth asphyxia; n = 1. ^cInfections/autoimmunity; n = 3, Langerhans cell histiocytosis; n = 6, transfusion-dependent thalassemia; n = 3, brain neoplasm and treatment hereof; n = 3, leukemia/lymphoma and treatment hereof; n = 6, other; n = 10.

Figure 2.

The age distribution at diagnosis of congenital combined pituitary hormone deficiency (cCPHD). The age at cCPHD diagnosis was defined as the age on the date of the second hormone deficiency diagnosis (n = 123).

Figure 3.

The incidence of congenital combined pituitary hormone deficiency (cCPHD) in Denmark diagnosed before age 18 years. The figure only includes patients with cCPHD who were born in Denmark and diagnosed before age 18 years (n = 116). Solid columns represent the incidence estimations that are not influenced by right truncation, as all patients born in the period 1996-2002 have turned 18 years old by the end of the observation period. Hatched columns represent incidence estimations that may be influenced by right truncation.

Figure 4.

The incidence of congenital combined pituitary hormone deficiency (cCPHD) in Denmark diagnosed before age 1 year (A), and at age 1-17 years (B). Solid columns represent the incidence estimations that are not influenced by right truncation, as all patients born in these years had turned 1 year (A), or 18 years (B) by the end of the observation period. Hatched columns represent incidence estimations that may be influenced by right truncation.