Combined Pituitary Hormone Deficiency Patients Research Articles

Genetic Screening of Combined Pituitary Hormone Deficiency: Experience in 195 Patients

Mutations in transcription factors result in combined pituitary hormone deficiency (CPHD). A genetic screening strategy, based on endocrine and neuroradiological phenotype according to published knowledge, was applied to establish the prevalence of gene defects in each category of patients and provide a useful framework for clinicians to determine the genetic etiology and recurrence risks for individuals and families. One hundred ninety-five CPHD patients from the international GENHYPOPIT network were studied, according to their phenotype, for POU1F1, PROP1, LHX3, LHX4, and HESX1. Patients selected had two pituitary hormone deficiencies or at least one deficiency with intracerebral malformations. Total prevalence of mutations was 13.3 and 52.4% in 20 patients with familial CPHD history. No mutation of HESX1 was observed in 16 patients harboring septooptic dysplasia. A mutation of LHX4 gene, previously reported, was found in one familial case from 39 patients bearing pituitary stalk interruption syndrome. In 109 patients without extrapituitary abnormalities, 20 had PROP1 mutations, including eight patients with a family history of CPHD. Among 20 patients without pituitary stalk interruption syndrome, no LHX3 gene defect was found, even with a neck rotation deficit. One POU1F1 gene defect was found in one patient presenting the rare postpubertal association of thyrotroph (TSH deficiency) and somatotroph (GH deficiency) deficits. Mutation of PROP1 gene remains the first to be looked for, and POU1F1 mutations should be sought in GH deficiency and TSH deficiency postpubertal population without extrapituitary malformations. Identification of gene defects allows early treatment of any deficit and prevention of their potentially fatal consequences. Genotyping appears highly beneficial at an individual and familial level.

The role of growth hormone in determining birth size and early postnatal growth, using congenital growth hormone deficiency (GHD) as a model

The role of GH in early human growth is unclear. Congenital GH deficiency (CGHD) provides a useful tool to explore this putative role. We have assessed the effects of CGHD on birth size and early postnatal growth, and the further impact of the presence of additional pituitary hormone deficiencies and midline brain defects on these parameters. Weight, length and BMI expressed as standard deviation scores (SDS), over the first two years of life, were retrospectively compared in 44 GH-deficient children (M:F 26 : 18). Thirty-eight of 44 patients underwent GH provocation testing and all patients had neuro-imaging of the brain. The patients were divided into three groups of increasing phenotypic complexity {group A [n = 12, isolated GHD, no midline defects], group B [n = 10, combined pituitary hormone deficiency (CPHD); no midline defects], group C (n = 22, CPHD with midline defects)}. Mean birth weight, length and BMI SDS were -0.4, -0.9 and +0.1 SDS, respectively. The differences were significant for weight (P = 0.03) and BMI (P = 0.003), but not length (P = 0.3) SDS, between groups A and C. Of the three groups, group A had a lower weight and BMI SDS than group C. The prevalence of postnatal complications (n = 25) was significantly different in the three groups [group A (8%), group B (80%), group C (73%); P < 0.001] and particularly between patients with isolated GH deficiency (IGHD) (group A) and CPHD (groups B and C; P < 0.0001). No patients in group A presented with neonatal hypoglycaemia as compared with 70% of those in group B and 59% in group C (P = 0.001). A reduced length SDS was observed in all patients within 6 months of birth and the reduction was greatest in group B (P = 0.03). Group C remained significantly (P < 0.05) heavier at 12, 18 and 24 months compared to group A. BMI SDS was significantly (P < 0.05) greater at all study points in CPHD patients (groups B and C) as compared with IGHD. Serum GH concentrations at testing did not correlate significantly with birth length (r = -0.08, P = 0.7), birth weight (r = -0.08, P = 0.6) or the age at induction of GH treatment (r = 0.12, P = 0.5). There were no significant differences between peak serum GH concentrations in patients in groups A (7.8 +/- 6.3 mU/l), B (3.9 +/- 4.8 mU/l) or C (8.7 +/- 5.4 mU/l). Length, weight and BMI data from our study groups suggest that GH per se has a minimal effect on intrauterine growth but a significant effect during the infancy period. Early growth may also be influenced by the complexity of the hypopituitary phenotype reflected by the presence of additional pituitary hormone deficiencies and midline forebrain defects.

Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD)

Mutations within the pituitary-specific paired-like homeobox gene PROP1 have been described in 50-100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1. Patients with congenital hypopituitarism were recruited from the London Centre for Paediatric Endocrinology as well as several national and international centres. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to panhypopituitarism. Clinical data, including endocrine and neuro-radiological studies were obtained from patient records, and DNA was collected and screened for mutations within PROP1 using PCR and single-stranded conformation polymorphism (SSCP) analysis. Positive results on SSCP were sequenced directly. The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1.1%) than in familial cases (29.5%). PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia. We describe the waxing and waning of a pituitary mass over 20 months in association with a PROP1 mutation that is predicted to lead to complete loss of function. Additionally, we have identified a possible founder mutation in CPHD patients from the Indian subcontinent. PROP1 mutations are rare in sporadic cases of CPHD, although the prevalence rises if there is a positive family history or if the patients are carefully selected with respect to the endocrine and neuroradiological phenotype. There is considerable phenotypic variability in families with the same mutation, indicating the role of other genetic or environmental factors on phenotypic expression. Finally, the pituitary enlargement that is observed in patients with PROP1 mutations can wax and wane in size before eventual involution.