Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

Abstract

ContextThe international GENHYPOPIT network collects phenotypical data and screens genetic causes of non‐acquired hypopituitarism.AimsTo describe main phenotype patterns and their evolution through life.DesignPatients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.ResultsAmong 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.ConclusionThis large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long‐term follow‐up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: A single center experience from over 30 years

“…38,67 In contrast to the results by Jullien et al, neonatal genital phenotype was in our series a cue to early diagnosis of CPHD. 17 Also, the boys with a neonatal genital phenotype developed GHD and most of them could be verified with gonadotropin deficiency. In our series, patients with combinations of defined neonatal features of CPHD were identified early.…”

Congenital hypopituitarism due to novel compound heterozygous POU1F1 gene mutation: A case report and review of the literature

“…To date, there are only few reports on congenital hypopituitarism with POU1F1 gene mutation ( Fig. 3 , Table 1 ) [ 3 , 4 , [6] , [7] , [8] , [9] , [10] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] ]. In the earlier reports, the R271W mutation was firstly recognized within numerous patients, suspicious as a hot spot [ 8 , [12] , [13] , [14] , [15] , [16] ].…”

“…There are many genes that are considered as transcription factors to participate in signaling pathway of pituitary development accounting for 5–20% of congenital hypopituitarism. POU1F1 mutation accounts for 0.4–20% in these mutations [ [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] ]. Here, we report an 8-month-old patient of novel compound heterozygous POU1F1 gene mutation leading to congenital hypopituitarism, with the presentation of hypoglycemia, failure to thrive, and developmental delay.…”

Intronic variant in POU1F1 associated with canine pituitary dwarfism

“…CPHD prevalence is 1:8000, and cases can be categorised into syndromic and non-syndromic groups according to the molecular defects (De Rienzo et al 2015). A recent genotype screening of the known CPHD genes in ~ 1200 patients revealed only 7.3% and 29.5% discovery rates in sporadic and familial cases, respectively (Jullien et al 2020). Indeed, the molecular aetiology remains unexplained in most patients despite the accelerating speed of gene discoveries facilitated by high throughput sequencing.…”