HIST1H1E syndrome with deficiency in multiple pituitary hormones

Highlights

● We report the first case of HIST1H1E syndrome with hyposecretion of several pituitary hormones.

● De novo frameshift H1-4 mutations (c.441dup: p. (Lys148Glnfs*48)) were detected.

● A mutation at the C-terminus of H1-4 may result in DNA CpG hypomethylation and in nonspecific enhancement of gene expression in the central nervous system.

Introduction

HIST1H1E syndrome (MIN #617537), also known as Rahman syndrome, is a rare autosomal-dominant intellectual disability syndrome caused by monoallelic pathogenic frameshift variants affecting the C-terminal domain of the H1-4 gene (MIM*142220) (NM_005321) (1, 2). This syndrome is characterized by overgrowth, distinctive facial features (i.e., full cheeks, high hairline, hypertelorism, telecanthus, deep-set eyes, down-slanting palpebral fissures, and micrognathia), mild to severe intellectual disability, and behavioral problems (1). However, Takenouchi et al. reported a patient who did not show skeletal overgrowth, but had a short stature as an adult, and the physical features were essentially the same as those observed in patients with HIST1H1E syndrome (3). We report a case of HIST1H1E syndrome in a patient with a short stature and deficiency in multiple pituitary hormones.

Case Report

The patient was born at 38 wk and 4 d by Cesarean section, with a weight of 3,012 g and a length of 48.0 cm, which was appropriate for the gestational age. She stayed in the neonatal intensive care unit for one month owing to respiratory distress, and was subsequently diagnosed with spastic cerebral palsy. No abnormalities were noted in newborn screening. Dysmorphic features and congenital anomalies included congenital amblyopia, a right abducted foot, a left adducted foot, and hearing loss. The patient demonstrated a severe intellectual disability at 3 yr of age, along with a history of global developmental delay. In particular, she was unable to walk independently at the 7 yr of age. The patient’s growth curve is shown in Fig. 1A. At 8 yr old, the patient presented to our hospital with a short stature and growth retardation. Her weight was 14 kg (–2.4 standard deviations), height was 95.3 cm (–5.6 standard deviations), pulse rate was 84 beats/min, temperature was 36.4°C, and blood pressure was 102/64 mmHg. She had characteristic facial features of a broad forehead, slightly wide-spaced eyes, a high hairline, an inferior palpebral fissure, esotropia, and a low flat nasal bridge (Fig. 1B). Consent was obtained from the parents for publication of an image of the patient’s face. In addition, she showed malocclusion, scoliosis, camptodactyly, limited speech, and hearing loss. Her behavior was abnormal, often including activities such as air-swallowing, hand-rubbing, and fluttering limbs. Hypothyroidism was detected (free thyroxine concentration, 0.65 ng/dL; reference range, 0.7–1.48 ng/dL; triiodothyronine concentration, 61.6 ng/dL; reference range, 80–160 ng/dL; thyroid-stimulating hormone concentration, 2.24 mIU/L, reference range: 0.35–4.94 mIU/L). Her cortisol levels by contrast, were normal (13.3 μg/dL; reference range, 3.0–19.0 μg/dL) as well as her adrenocorticotropic hormone (28.4 pg/mL; reference range, 11–29 pg/mL), while those of insulin-like growth factor-1 (28 ng/mL; reference range, 111–438 ng/mL) and E₂ (less than 5 pg/mL) were low. Growth hormone (GH) stimulation tests showed a GH deficiency (peak GH in an insulin stimulation test, 1.72 ng/mL; peak GH in an arginine stimulation test, 1.45 ng/mL).

Fig. 1.

Growth curve and facial photograph of the patient. A: Growth curve of the patient. Stunted growth was reversed by continuous administration of levothyroxine and growth hormone starting at 9 yr of age. B: Facial photograph of the patient. A broad forehead, high hairline, slightly wide-spaced eyes, narrow eyelid fissures, low flat nasal bridge, sparse eyebrows, and uneven teeth are shown.

A brain magnetic resonance imaging scan showed a hypoplastic corpus callosum, a slender septum pellucidum, cerebellar vermis hypoplasia, and a hypoplastic pituitary gland. Her bone age at chronological age of 8.0 yr was delayed to 4.6 yr, and her bone mineral density was decreased (0.364 g/cm²; reference range, 0.8–1.2 g/cm²). On the basis of these findings, the patient was diagnosed with central hypothyroidism and GH deficiency, and was treated with continuous levothyroxine and GH. The therapeutic effect of GH was remarkable, and the patient’s height increased. As her development improved, she was able to walk without support by 10 yr of age. At 14 yr of age, hypogonadotropic hypogonadism was diagnosed after a luteinizing-releasing hormone (LHRH) stimulation test. In the LHRH stimulation test, the patient’s pre-stimulus values for LH and FSH were 0.3 mU/mL and 1.3 mU/mL, respectively, and peak values were 0.6 mU/mL, and 4.7 mU/mL, respectively. Conjugated estrogen treatment was initiated and puberty was achieved.

Mutation Analysis

At 13 yr of age, the patient underwent whole exome sequencing as well as filtering analyses, and a de novo frameshift H1-4 pathogenic variant (NM_005321.3:c.441dup: p.(Lys148Glnfs*48)) was identified (Fig. 2B). Thus, a diagnosis of HIST1H1E syndrome was made. A functional analysis was also performed using protein function prediction software (NetPhos - 3.1 - Services - DTU Health Tech. Lyngby, Denmark). NetPhos, which is a software that predicts phosphorylation sites (probably phosphorylated in vivo) was used to determine H1-4 linker protein function. We found that the protein coded by the mutated gene [c.441dup:p. (Lys148Glnfs*48)] had more phosphorylation sites behind the mutated site (red arrow in Fig. 2B) than the normal non -mutated protein (Fig. 2A). The sum of phosphorylation potentials (vertical axes in Figs. 2A and B) was higher in the protein coded by the mutated c.441dup:p. (Lys148Glnfs*48) than that coded by the wild type, which suggested that her cells-were more likely to express euchromatin and that the cell cycle was enhanced.

Fig. 2.

Phosphorylated potentials of the H1-4 protein. A: Putative steric structure of the H1-4 protein encoded by the wild type gene; B: Putative abnormal steric structure of the H1-4 protein encoded by frameshift mutations in c.441dup:p. in the patient.-NetPhos, which is a software that predicts protein function by predicting the phosphorylation sites (probably phosphorylated in vivo), was used to determine H1-4 linker protein function. NetPhos shows that c.441dup:p. (Lys148Glnfs*48) has more phosphorylation sites behind the mutated site (red arrow) than the wild-type protein. The red frame shows the C-terminal active site of phosphorylation reported in past literature.

Discussion

While previous cases of HIST1H1E syndrome reported overgrowth and intellectual disability, Takenouchi et al. (4) suggested that skeletal overgrowth may not be an essential feature of this syndrome. In their cohort study of five patients, four patients showed a decreased height over time, and three had an above average height that eventually decreased to average or below average as they aged. No skeletal overgrowth was observed. These previous findings suggest that overgrowth is not the main clinical manifestation of HIST1H1E syndrome.

To date, only hypothyroidism has been reported as an endocrinological abnormality. To the best of our knowledge, this is the first reported HIST1H1E syndrome case of hyposecretion of several pituitary hormones caused by hypoplasia in in the hypothalamic–pituitary axis. In a previous study involving 48 cases, 20 had central nervous system malformations and 5 had hypothyroidism, 4 of which were associated with central nervous system malformations. One of the five cases of hypothyroidism was associated with hypoplasia of the anterior pituitary gland, clearly indicating an association between central nervous system malformations and endocrinological abnormalities (4). Burkardt et al. reported highly varied findings among their 14 subjects with MRI data (5). The common findings of brain MRI include hypoplastic corpus callous, delayed myelination and ventriculomegaly. Pituitary hypoplasia has been reported in one case of the de novo, c.360_361insA, (p.Ala123Glyfs*73) mutation. That case was associated with hypothyroidism, and the other pituitary functions of that case are unknown. A mutation at the C-terminus of H1-4, which is truncated and functionally nearly identical, causes DNA to loosen and become euchromatin. This process results in DNA CpG hypomethylation and a specific DNA hypomethylation signature, resulting in nonspecific enhancement of gene expression in the central nervous system (2). The suggested relationship between genetic variation and the clinical presentation of the endocrinological disorder in our patient with HIST1H1E syndrome warrants further studies to clarify whether the mutation in H1-4 gene causes variable clinical phenotypes.

Conflict of interests: The authors have no conflicts of interest or financial assistance to disclose.