HIST1H1E syndrome with type 2 diabetes

Abstract

A 20-year-old woman was referred to the diabetes clinic with type 2 diabetes diagnosed at the age of 19. Her body mass index was 31.4 kg/m², HbA1C was 76 mmol/mol, GAD antibodies were negative with a detectable C-peptide. She had a characteristic facial appearance with widespread eyes, posterior hairline suggesting a facial gestalt and abnormal dentition. She also had hypothyroidism, mild intellectual disability, primary amenorrhoea and patent ductus arteriosus. Karyotyping reported normal 46XX karyotype. Genetic testing revealed a pathogenic variant in the gene encoding the HIST1H1E protein which confirmed her diagnosis of HIST1H1E syndrome. Type 2 diabetes has not been reported in previous cases of HIST1H1E and so this is the first reported case of type 2 diabetes with HIST1H1E syndrome.

Background

HIST1H1E syndrome is a rare intellectual disability (ID) syndrome, with 47 cases reported in the literature,^1–5 caused by protein-truncating variants (PTVs) in the histone gene cluster 1 located at chromosome 6p22.2 which plays a role in DNA replication. In addition to ID, it has been associated with a characteristic facial gestalt, hypotonia, cardiac and skeletal abnormalities and hypothyroidism.¹ The disease was initially described as an overgrowth syndrome,² however, latest reports do not confirm this association. To our knowledge, there have been no previous cases in the literature reporting an association with diabetes. We are writing this report to share our endocrinological experience in the management of HIST1H1E syndrome.

Case presentation

A 20-year-old Caucasian woman was referred to the young adult diabetes clinic at our tertiary centre with type 2 diabetes diagnosed 1 year previously at the age of 19 years. At time of diagnosis, she was asymptomatic except for fatigue. Her body mass index (BMI) was 31.4 kg/m². She had a characteristic facial appearance with widespread eyes, posterior hairline suggesting a facial gestalt and abnormal dentition. She also had a background history of hypothyroidism, mild ID, primary amenorrhoea, patent ductus arteriosus, Bell’s palsy, paroxysmal dyskinaesia and >100 skin naevi. There was no family history of diabetes or other related disorders. On clinical examination, she had delayed sexual development with small breasts, minimal axillary and pubic hair and no clinical signs of insulin resistance.

Investigations

She had random plasma glucose of 11.1 mmol/L and an abnormal oral glucose tolerance test with a fasting blood glucose of 9.6 mmol/L and a 2-hour postprandial level of 19.6 mmol/L. Urine and blood ketones were negative. HbA1C at the time of diagnosis was 76 mmol/mol (9.1%) and this had risen over time to 93 mmol/mol (10.7%) due to difficulty in compliance with glucose lowering medications. However, more recently with an improvement in compliance, the HbA1c had fallen to 44 mmol/mol (6.2%). Antibody screen for type 1 diabetes was negative. C-peptide was detectable at 1.8 ug/L (reference range 1.4–4.4) 5 years after diagnosis. Total cholesterol was 4.79 nmol/L (reference range 0–5) with triglyceride 2.03 nmol/L (0–1.9), LDL 2.61 and HDL 1.26 nmol/L (1–1.7). She had normal serum 46XX karyotype. Genetic testing at the time of diagnosis did not reveal any abnormality however further genetic testing 9 years later detected a pathogenic variant in the gene encoding the carboxy terminal part of the HIST1H1E protein. In regard to the primary amenorrhoea, the pituitary–gonadal axis was normal with FSH 6 U/L (reference range 3.5–12.5), LH 4.5 U/L (2.4–12.6), detectable oestradiol at 82.7 pmol/L (45–854) and normal serum prolactin of 248 mIU/L (reference range 71–566). Her thyroid function was normal on levothyroxine with a free T4 of 10.3 pmol/L (7-16) and TSH 1.38 mIU/L (0.5–4.2). Transabdominal and transvaginal ultrasound of the pelvis was also normal. Wrist X-ray at the age of 16 reported normal bone age consistent with the chronological age of the patient. Echocardiogram was performed for follow-up of a previously repaired patent ductus arteriosus and this showed mild aortic regurgitation. MRI scan of the brain was normal.

Differential diagnosis

The phenotype and the presence of hypothyroidism, diabetes, amenorrhoea and abnormal limb movement raised the suspicion of Woodhouse-Sakati syndrome, however, this was ruled out by genetic testing. Pallister-Killian syndrome is considered as another differential as it manifests with ID, prominent forehead with sparse scalp hair anteriorly and cardiac anomalies. However in Pallister-Killian syndrome karyotyping reveals a 47 chromosome pattern due to trisomy of chromosome 12p.⁶

Treatment and outcome

The patient was treated initially with metformin 500 mg two times per day, followed by gliclazide MR 60 mg daily, linagliptin 5 mg daily and empagliflozin 10 mg once a day. She was intolerant of high dose metformin due to gastrointestinal upset and refused injectable therapies. As her compliance with her medications improved her HbA1c fell significantly. Gliclazide medication was stopped and her HbA1c remained stable at 44 mmol/mol while on metformin 500 mg two times per day, linagliptin 5 mg and empagliflozin 10 mg daily. The patient has been following at our centre for the last 10 years and is now 30 years old. To date, no diabetes related complications have been detected. Hypothyroidism was managed with levothyroxine 100 μg 5 days a week and 50 μg on the other 2 days of the week.

Discussion

HIST1H1E syndrome also known as Rahman syndrome is a rare ID disorder caused by PTVs in the histone gene cluster 1, member E, HIST1H1E located in chromosome 6p22.2. The variants result in an autosomal dominant disease yet the degree of penetrance is yet to be identified.⁵

It was first described by Tatton-Brown et al as an ID and overgrowth syndrome. Takenouchi et al reported a case without overgrowth. Burkardt et al reported a case series of 30 individuals describing the phenotype of HIST1H1E syndrome. All of the individuals had ID with variable severity but mostly moderate ID. Flex et al reported that the aberrant function of this gene is associated with accelerated ageing.⁷ Facial gestalt which was also present in all cases included a high hairline, full low cheeks, bitemporal narrowing, frontal bossing and deep-set eyes.¹

The other features of HIST1H1E syndrome include abnormal brain MRI findings, cardiac anomalies, hypothyroidism, hypotonia, behavioural changes, abnormal dentition, skeletal abnormalities and cryptorchidism in males. There have been two cases of afebrile seizures.⁶ Ophthalmological abnormalities (such as strabismus and astigmatism) and sensorineural hearing loss have also been reported.

Woodhouse-Sakati syndrome shares some of the features such as ID, hypothyroidism, alopecia, sensorineural hearing loss and brain MRI abnormalities.⁸ Diabetes had been found in about 66% of cases of the syndrome and typically present in late childhood to early adulthood age.

In Pallister-Killian syndrome, there are again varying degrees of ID and developmental delay as well as facial anomalies, congenital heart disease and seizures. However, the fronto-temporal balding is more prominent in childhood and improves with age. Karyotyping helps to differentiate between the two syndromes as the latter displays a 47 chromosome karyotype as a result of trisomy (or hexasomy in 9.1%) of chromosome 12p.⁹

To our knowledge, there have been no previous reports of diabetes with HIST1H1E syndrome and therefore our case is considered the first patient to develop diabetes with this syndrome. In a case–control study, Tian et al reported an increased risk of type 2 diabetes in patients with CDKAL1 gene polymorphism mapped to chromosome 6p22.3 as a result of loss of insulin response to hyperglycaemia.¹⁰ Whether PTVs frame shift in chromosome 6p22.2 in HIST1H1E results in similar pathogenesis remains unknown. The HIST1H1E syndrome was initially described as an overgrowth syndrome and in fact most of the reported cases have a raised BMI which may increase the risk of insulin resistance and diabetes. Additionally, while HIST1H1E syndrome is an ID disorder and ID disorders may have an association with abnormal eating behaviours the latter was not reported in the other probands. When comparing this case to the previous cases reported, our patient is considered one of the oldest cases and it remains unclear whether diabetes is part of the syndrome as patients get older or not. In our patient, despite leading a healthy lifestyle (with the assistance of a senior dietician) following healthy eating habits and regular exercise by swimming her diabetes has progressed requiring the addition of glucose-lowering medications over the years. Therefore, we adopted the standards of type 2 diabetes care. During the 11 years of follow-up in our institute, the patient was treated with metformin, sulphonylurea, DPP-4 inhibitor and SGLT-2 inhibitor along with education and lifestyle modification advice and this has resulted in excellent glycaemic control with no observed diabetes-related complications. Primary amenorrhoea is also considered as a new incidence in the syndrome. Further review and follow-up of the other prepubertal cases may clarify if there is any correlation in the future.

In conclusion, further studies are needed to clarify the association of diabetes with HIST1H1E. In general, obesity which appears to be prominent in this disorder is a risk factor for diabetes. It is, therefore, recommended to screen obese children at the age of 10 for diabetes if they have two other risk factors including family history, high-risk ethnicity (Asian, black, Hispanic, Native American or Pacific Islander), maternal history of diabetes or gestational diabetes or clinical signs of insulin resistance.

Patient’s perspective.

(Courtesy to the patient’s parents)

Our daughter, who is now 30-year-old, was always much slower in reaching life progress/milestones compared to her older brother. Despite her obvious learning difficulties, we made sure she stayed in main stream school up to the age of 19. She also attends 3rd level college of further education. Her reading ability is very good, however her ability to understand what she reads is always a problem. Her memory for names, faces, music groups and complicated computer passwords remains excellent. She can cycle, walk but not run as she is prone to falling. We are doing our best to keep her weight under control through diet and exercise. She is very sociable and has a very friendly approach to everyone and for that reason she requires supervision to ensure that she is not abused or taken advantage of. The past 30 years has been a long and sometimes frustrating journey and there remains several medical and learning issues which will continue to dictate and influence her future. As it is most likely she will outlive both her parents it is important that we ensure she continues to live in a safe, caring environment.

Learning points.

• HIST1H1E syndrome is a rare genetic disorder with varying degrees of intellectual disability and characteristic facial gestalt.

• It is also associated with cardiac, neurological, behavioural abnormalities and hypothyroidism.

• The association with diabetes as in this case remains unclear.

• Screening for diabetes is recommended in obese children with two additional risk factors.

• Our case was well managed using standard care for type 2 diabetes through a multidisciplinary approach using lifestyle modifications and oral hypoglycaemic medications.

Ethics statements

Patient consent for publication

Obtained.