Endocrine Abstracts

Introduction: HIST1H1E syndrome is a rare disorder caused by a de novo gene mutation encoding for histone H1-4 affecting a whole range of cellular processes. The phenotype is dominated by neurodevelopment disorders and facial deformities. Endocrinopathies and diabetes mellitus are not the main clinical features. The case of a woman with HIST1H1E syndrome associated with diabetes mellitus and panhypopituitarism is presented.

Case presentation: A 19-year-old woman was referred to the endocrinology department because of primary amenorrhea and absence of secondary sexual characteristics. At the age of 12 years she was diagnosed with HIST1H1E syndrome. Growth curve was not available and height at the moment of consultation was 156 cm and BMI 20 kg/m². Pituitary function revealed central hypothyroidism, hypogonadotropic hypogonadism and low IGF-1. GH deficiency was confirmed with an insulin tolerance test. Cortisol deficiency was excluded and there were no arguments for AVP deficiency. Reviewing a blood sample at the age of 9 years, a normal thyrotropic axis was measured. MRI of the pituitary was normal. X-ray of the hand showed an almost closed growth plate. Bone density showed osteoporosis. The blood sample showed hyperglycaemia with an HbA1c of 13.9% (128 mmol/mol) and low c-peptide (0.08 nmol/l). Insulin therapy was started.

Conclusion: HIST1H1E syndrome is rare as only 52 cases have been described in the literature. Endocrinopathies are rarely associated with this syndrome as only 6 previous cases had hypothyroidism. In 2023 the first case of a young girl with HIST1H1E syndrome and short stature due to panhypopituitarism (TSH, LH/FSH, GH deficiency) was published. MRI showed a hypoplastic pituitary gland. We present the second case of a woman with panhypopituitarism (TSH, LH/FSH, growth hormone deficiency), associated with HIST1H1E syndrome after presenting with primary amenorrhea. Corticotropic axis is preserved in both cases. We hypothesize the dysfunctional histones lead to a PROP1-related combined pituitary hormone deficiency. However, it is unclear why the other published cases did not show hypopituitarism except for these cases concern children and pituitary deficiency may not have already developed. Diabetes mellitus type 2 has previously been described in only one 19-year-old woman with HIST1H1E syndrome. Our case has an impaired insulin secretion questioning the possible association of the pathogenic histone variants with loss of β cell function. Given the rareness of this syndrome, it is however uncertain if clinical features as hypopituitarism and diabetes mellitus are related to the dysfunctional histones or are incidental findings.