Hyperprolactinemia, hyperandrogenemia, pituitary adenoma, and metabolic disorders in Wiedemann-Steiner syndrome: a case report

Abstract

Background

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by variants in the lysine-specific methyltransferase 2 A (KMT2A) gene. It is characterized by developmental delay, intellectual disability, hypertrichosis, growth retardation, and distinctive facial appearance. Reports on adult patients with WSS remain limited.

Case presentation

We report the case of a 26-year-old woman with WSS who presented with oligomenorrhea for 11 years and irregular menstruation for 2 years. Since birth, she had hypertrichosis on her back and extremities, growth and development retardation, and brachydactyly. She had been receiving antipsychotic treatment with risperidone and trihexyphenidyl for the past two years. Laboratory evaluation revealed hyperprolactinemia (prolactin 1062.96 mIU/L; reference range 59.00–619.00 mIU/L), hyperandrogenemia, impaired glucose tolerance, insulin resistance, and hyperuricemia. Magnetic resonance imaging showed a pituitary microadenoma, which was confirmed as non-functioning following comprehensive pituitary hormone assessment. Whole-exome sequencing identified a de novo variant in the KMT2A gene: c.173dupC (p.Ala59Glyfs*88). Regarding management, risperidone and trihexyphenidyl were switched to aripiprazole on psychiatric advice. Half a month after the medication change, prolactin decreased to 124.32 mIU/L and remained at 129.73 mIU/L six months later.

Conclusions

Clinicians should be aware of the risk of antipsychotic-induced hyperprolactinemia in patients with WSS receiving such treatment. Moreover, endocrine-related issues warrant greater attention in the clinical management of these patients, particularly in adulthood.

Background

Wiedemann-Steiner syndrome (WSS, MIM 605130) is a rare autosomal dominant disorder first described by Wiedemann et al. in 1989 [1], with Steiner et al. later proposing it as a distinct syndrome approximately a decade later [2]. Although the exact incidence of WSS remains unknown, at least 250 cases have been documented worldwide as of 2023, with an estimated prevalence of 1/25,000 to 1/40,000 [3]. The syndrome is caused by pathogenic variants in the lysine-specific methyltransferase 2 A (KMT2A) gene, which encodes a transcriptional coactivator belonging to the lysine methyltransferases family [4]. KMT2A plays a critical role in early development by regulating gene transcription through chromatin opening or closure [5]. WSS is a multisystem disorder characterized by developmental delay, intellectual disability, hypertrichosis, growth retardation, and a distinctive facial appearance, including thick eyebrows, long eyelashes, hypertelorism, wide nasal bridge, and thin upper lip [6]. Advances in genetic testing have led to an increased identification of WSS, with age at diagnosis ranging from 4 months to 46 years; approximately 85% of affected individuals are diagnosed before the age of 18 years [6]. However, due to the paucity of adult patients, data on long-term follow-up, clinical management, and prognosis in this population remain limited.

Here we report a case of WSS in a 26-year-old unmarried woman who presented with an 11-year history of oligomenorrhea and a 2-year history of irregular menstruation. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine (SAHZU) (2022-0056). By presenting this case, we aim to highlight the importance of long-term management and endocrine surveillance in patients with WSS.

Case presentation

The affected individual was born at full term via vaginal delivery, with a birth weight of 1.9 kg and an unrecorded birth length. Since birth, she experienced feeding difficulty, delayed developmental milestones, poor learning ability, growth retardation, intellectual disability, and recurrent respiratory infections. Menarche occurred at age 15, with a menstrual cycle of approximately 90 days, a menstrual period of 6–7 days, and normal menstrual flow. Two years ago (at age 24), her menstruation became irregular, characterized by delayed cycles and hypomenorrhea. Her last menstrual period had occurred approximately 80 days ago. Half a month ago, she visited a local clinic because of hypomenorrhea. Sex hormone testing revealed elevated prolactin (PRL) at 1280.48 mIU/L (reference range: 70.81–566.46 mIU/L). She denied any associated symptoms such as weakness, headache, visual field defects, polydipsia, or polyuria. Regarding her mental health, she had intermittent episodes of irritability and aggressive behavior beginning at age 16. Two years ago, she was started on risperidone (1 mg nightly) and trihexyphenidyl (2 mg twice daily), and her mental state has since remained stable. She completed junior high school and is currently unemployed. Her father and mother are 162 cm and 158 cm tall, respectively, and report no consanguineous marriage. Her 18-year-old younger sister is 155 cm tall and has normal learning abilities.

Physical examination revealed a height of 137 cm (Z score − 4.39), a weight of 43 kg (Z score − 1.20), and a body mass index (BMI) of 22.9 kg/m². She exhibited dental crowding, long philtrum, wide nasal bridge, hypertelorism, long eyelashes, thick eyebrows, low-set ears, short neck, hypertrichosis on back and extremities, brachydactyly, lactation, and an abnormal wadding gait (Fig. 1).

Fig. 1.

Clinical manifestations of the affected individual. (A ~ B) Short neck. (C) Brachydactyly, particularly at the fifth finger

Table 1 summarizes the results of the main laboratory evaluations. Regarding metabolic parameters, levels of lipoprotein A and uric acid (UA) were higher than the reference range. Glycated hemoglobin A1c (HbA1c) was at to 6.3%. Oral glucose tolerance test (OGTT) revealed normal levels of fasting plasma glucose (FPG), fasting insulin (FINS) and fasting C-peptide (FCP), whereas 2-hour postprandial plasma glucose (2hPG), 2-hour postprandial insulin (2hINS), and 2-hour postprandial C-peptide (2hCP) increased to 10.69 mmol/L, 1975.84 pmol/L, and 5.47 nmol/L, respectively. Based on homeostasis model assessment (HOMA) proposed by Matthews et al. [7], HOMA-insulin resistance (HOMA-IR) was calculated by the formula of “FINS (pmol/L)×FPG (mmol/L)/135”, yielding a value of 3.25 for the patient. Bone metabolism-related markers were as follows: total 25-hydroxy vitamin D (T25OHD) was 11.1 ng/ml, parathyroid hormone (PTH) was 82.9 pg/ml, and both C-terminal cross-linking telopeptide of type I collagen (β-CTX) and procollagen type 1 N-terminal pro-peptide (P1NP) were mildly elevated. Regarding pituitary hormone axes, PRL, testosterone, and dehydroepiandrosterone sulfate (DHEA-S) were higher than reference ranges, with values of 1062.96 mIU/L, 2.09 nmol/L, and 13.14 µmol/L, respectively. Thyroid function, hypothalamic-pituitary-adrenal axis, growth hormone, and insulin-like growth factor-1 were all within the normal limits. Furthermore, a mid-dose dexamethasone suppression test ruled out congenital adrenal hyperplasia (CAH), with 17-hydroxyprogesterone suppressed from 0.63 nmol/L to 0.41 nmol/L (suppression rate 34.9%) and testosterone from 2.07 nmol/L to 1.63 nmol/L (suppression rate 21.3%), neither meeting suppression criteria for CAH.

Table 1.

Biochemical results of the patient at baseline

Metabolic parameters	Value	Reference range	Hormones of pituitary axes	Value	Reference range
PG (fast)	5.20 mmol/L	3.89–6.11 mmol/L	GH	0.07 ng/ml	< 4.8 ng/ml
PG (OGTT 2 h)	10.69 mmol/L	-	IGF-1	148.0 ng/ml	84.0-259.0 ng/ml
Insulin (fast)	84.3 pmol/L	20.9-174.1 pmol/L	PRL	1062.96 mIU/L	59.00-619.00 mIU/L
Insulin (OGTT 2 h)	1975.84 pmol/L	-	LH	11.60 IU/L	Follicular phase: 1.90–12.50 IU/L Luteal phase: 0.50–16.90 IU/L
C-peptide (fast)	0.60 nmol/L	0.27–1.28 nmol/L	FSH	7.62 IU/L	Follicular phase: 2.50–10.20 IU/L Luteal phase: 1.50–9.10 IU/L
C-peptide (OGTT 2 h)	5.47 nmol/L	-	Progesterone	5.25 nmol/L	Follicular phase: <4.45 nmol/L Luteal phase: 10.62–81.28 nmol/L
HbA1c	6.3%	4.0–6.0%	Estradiol	235.49 pmol/L	Follicular phase: 71.60-529.20 pmol/L Luteal phase: 204.80-786.10 pmol/L
TC	4.54 mmol/L	3.00-5.70 mmol/L	Testosterone	2.09 nmol/L	0.31–1.66 nmol/L
TG	1.63 mmol/L	< 1.70 mmol/L	DHEA-S	13.14 µmol/L	0.70-12.49 µmol/L
LDL-C	2.32 mmol/L	< 3.36 mmol/L	TSH	1.16 mIU/L	0.35–4.94 mIU/L
HDL-C	1.30 mmol/L	0.90–2.19 mmol/L	Triiodothyronine	1.96 nmol/L	0.98–2.33 nmol/L
Lp (a)	362 mg/L	< 300 mg/L	Free triiodothyronine	5.25 pmol/L	2.43–6.01 pmol/L
UA	466 µmol/L	154–357 µmol/L	Thyroxine	93.0 nmol/L	58.1-140.6 nmol/L
Serum calcium	2.28 mmol/L	2.11–2.52 mmol/L	Free thyroxine	12.87 pmol/L	9.01–19.05 pmol/L
Serum phosphorus	1.43 mmol/L	0.85–1.51 mmol/L	ACTH (8am)	22.7 pg/ml	7.2–63.3 pg/ml
ALP	98 U/L	30–120 U/L	ACTH (4pm)	6.2 pg/ml	-
T25OHD	11.1 ng/ml	20–50 ng/ml	ACTH (0am)	4.3 pg/ml	-
PTH	82.9 pg/ml	15.0–65.0 pg/ml	Cortisol (8am)	386.0 nmol/L	166.0-507.0 nmol/L
β-CTX	762.0 pg/ml	68.0-680.0 pg/ml	Cortisol (4pm)	126.5 nmol/L	73.8–291.0 nmol/L
P1NP	65.1 ng/ml	8.5-64.3ng/ml	Cortisol (0am)	33.2 nmol/L	-

The reference ranges of all mentioned parameters are acquired from the Department of Clinical Laboratory of SAHZU. Abbreviations: PG, plasma glucose; OGTT, oral glucose tolerance test; HbA1c, glycated hemoglobin A1c; TC, total cholesterol; TG, total glyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; Lp (a), lipoprotein a; UA, uric acid; ALP, alkaline phosphatase; T25OHD, total 25-hydroxy vitamin D; PTH, parathyroid hormone; β-CTX, C-terminal cross-linking telopeptide of type I collagen; P1NP, procollagen type 1 N-terminal pro-peptide; GH, growth hormone; IGF-1, insulin-like growth factor-1; PRL, prolactin; LH, luteinizing hormone; FSH, follicle stimulating hormone; DHEA-S, dehydroepiandrosterone sulfate; TSH, thyroid stimulating hormone; ACTH, adrenocorticotropic hormone. Bold indicates abnormal values

Radiological findings were as follows: X-ray demonstrated brachydactyly, fusion of the distal interphalangeal joint of the fifth finger, mild flat acetabulum, and flattened lumbar spine curvature (Fig. 2A ~ D). Pituitary magnetic resonance imaging (MRI) revealed a 2.7 mm × 3.2 mm hypoenhancing lesion in the right pituitary gland on post-contrast T1-weighted images, consistent with a pituitary microadenoma (Fig. 2E). A structural brain abnormality was also noted (Fig. 2F). Ultrasound examination revealed a left renal cyst and right nephrolith, while cardiac structure was normal. Pelvic ultrasound showed an endometrial thickness of 7.7 mm and normal ovarian morphology without evidence of polycystic changes. Dual-energy X-ray absorptiometry revealed bone mineral density (BMD) was 1.042 g/cm² (Z score 0.2) at the lumbar vertebrae 1–4, 0.669 g/cm² (Z score − 1.6) at the femoral neck, and 0.779 g/cm² (Z score − 1.0) at the total hip.

Fig. 2.

Radiological characteristics of the patient. (A) X-ray of the left hand, brachydactyly, fusion of the distal interphalangeal joint at the fifth finger (red arrow). (B) X-ray of the pelvis, mild flat acetabulum. (C ~ D) X-ray of thoracolumbar spine, the lateral image shows flattened lumbar spine curvature. (E) Coronal view of the pituitary MRI: pituitary microadenoma (red arrow). (F) Sagittal view of pituitary MRI: existence of hyperintensity at the posterior pituitary, structural brain abnormality. (G ~ H) Coronal and sagittal view of the follow-up MRI one year later: pituitary microadenoma (red arrow). Abbreviations: MRI, magnetic resonance imaging

We performed whole-exome sequencing (WES) on the patient and Sanger sequencing on her family members to confirm the genetic diagnosis. The results revealed a de novo variant in the KMT2A gene of the patient: c.173dupC (p.Ala59Glyfs*88). No pathogenic variants in KMT2A were detected in her parents or younger sister.

Therefore, the patient was diagnosed with the following conditions: Wiedemann-Steiner syndrome, hyperprolactinemia, hyperandrogenemia with probable polycystic ovary syndrome (PCOS), non-functioning pituitary adenoma, impaired glucose tolerance (IGT), insulin resistance, hyperuricemia, secondary hyperparathyroidism, vitamin D deficiency, short stature, a mental disorder, left renal cyst, and right nephrolith.

The patient’s treatment and follow-up were as follows. First, risperidone was first taken into account as the cause of hyperprolactinemia in this case. Following the psychiatrist’s recommendation, risperidone and trihexyphenidyl were switched to aripiprazole (5 mg once nightly). Half a month after the medication change, PRL decreased to 124.32 mIU/L and remained stable at 129.73 mIU/L six months later. Second, an attempt was made to address insulin resistance and IGT with metformin, but the patient developed nausea and vomiting, leading to its discontinuation. She was advised to engage in regular outdoor exercise and maintain a healthy diet. Six months later, repeat OGTT showed: FPG 5.72 mmol/L, 2hPG 10.85 mmol/L, FINS 69.7 pmol/L, 2hINS 984.28 pmol/L, FCP 0.55 nmol/L, and 2hCP 3.75 nmol/L. HbA1c had decreased to 6.1%, and HOMA-IR had improved to 2.95. Third, to address vitamin D deficiency, the patient was advised to increase sun exposure. After six months, the level of vitamin D rose to 21.1 ng/ml, and PTH almost descended to the upper limit of the normal range with a value of 65.79 pg/ml. Forth, follow-up MRI one year later revealed no significant change in the pituitary lesion (Fig. 2.G ~ H), and anterior pituitary hormone levels remained within normal ranges with no clinical signs of hypersecretion. These findings support the diagnosis of an incidental non-functioning pituitary microadenoma.

Discussion and conclusions

Here we reported an adult patient with WSS presenting with multiple endocrine disorders, including antipsychotic-induced hyperprolactinemia, oligomenorrhea, non-functioning pituitary adenoma, and insulin resistance. She exhibited characteristic facial features, growth retardation, and intellectual disability since birth, but the genetic diagnosis was not confirmed until the age of 26. This case highlights the importance of long-term management in WSS.

The c.173dupC variant in the KMT2A gene identified in this patient has been previously reported and confirmed as pathogenic [8]. Truncating mutations are the most common type of germline KMT2A mutations, including frameshift (37.8%) and nonsense (29.3%) variants [9]. KMT2A functions as an epigenetic “writer”, playing an essential role in histone H3 methylation and contributing to chromatin remodeling [10]. Haploinsufficiency is recognized as the central pathogenic mechanism underlying WSS [4]. Truncating variants in KMT2A lead to premature protein termination, resulting in a global reduction of methylation across various genes [4]. In contrast, missense variants predominantly occur in the CXXC domain, which binds unmethylated CpG dinucleotides and is critical for mediating the WSS phenotype [11]. RNA sequencing and pathway analysis in patient with WSS have implicated the endothelial nitric oxide (eNOS) and bone morphogenetic protein (BMP) pathways in hypertrichosis, while the eNOS and Wingless/Int-1 (WNT) pathways have ben associated with cognitive dysfunction [12].

In 2021, Sheppard et al. comprehensively characterized the genotypic and phenotypic spectrum of WSS in a diverse cohort of 104 affected individuals, reporting confirmed de novo variants in 55.8% of patients [9]. A literature review encompassing 248 cases identified hypertrichosis, intellectual disability, growth and developmental retardation, and distinctive facial features as the most prevalent manifestations of WSS [6]. The syndrome affects nearly all organ systems, including the neurological, endocrine, musculoskeletal, cardiac, gastrointestinal, genitourinary, ophthalmic, dental/oral, and immune systems [6, 9]. Several correlations between genotype and phenotype have been established, that is, loss of function variants are more likely associated with hypotonia, whereas non-loss of function variants are related to seizures [9]. Given the clinical overlap with other syndromes—such as Cornelia de Lange, Coffin-Siris, Kabuki, Rubinstein–Taybi, and Suleiman–El-Hattab syndromes—WSS must be considered in the differential diagnosis [9, 13]. A definite diagnosis of WSS still relies on genetic testing.

Notably, this patient with WSS presented with concurrent hyperprolactinemia, pituitary microadenoma, and hyperandrogenemia—a constellation of endocrine findings that adds to the limited literature on adult manifestations of WSS. First, regarding the etiology of hyperprolactinemia: the differential diagnosis includes physiological, pathological, and pharmacological causes [14]. In cases of symptomatic non-physiological hyperprolactinemia, it is recommended to exclude medication use, renal failure, hypothyroidism, and parasellar tumors [14]. The patient had been receiving risperidone, an antipsychotic known to cause hyperprolactinemia in over 30% of users due to its dopamine antagonist effect [15]. Following the switch from risperidone to aripiprazole, PRL levels normalized and remained stable—consistent with antipsychotic-induced hyperprolactinemia. This observation aligns with meta-analytic evidence suggesting that aripiprazole is effective in managing this side effect [16]. Second, based on the absence of clinical symptoms and normal anterior pituitary hormone levels, the pituitary microadenoma was considered an incidental non-functioning adenoma. Sheppard et al. summarized that abnormal pituitary MRI accounted for 63.6% (7/11) without detailed description among WSS patients [9]. Stolye et al. reported a case of WSS with hypoplastic anterior pituitary [17]. The incidental finding in our patient is consistent with its high prevalence in the general population. Third, although pelvic ultrasound showed normal ovarian morphology without polycystic changes, the patient’s history of oligomenorrhea since menarche, along with hirsutism and hyperandrogenemia, raises the possibility of polycystic ovary syndrome (PCOS). Therefore, PCOS cannot be excluded in this case.

Metabolic disorders are infrequently reported in patients with WSS. However, this patient presented with multiple metabolic abnormalities, including IGT, insulin resistance, hyperuricemia, elevated level of lipoprotein a, and vitamin D deficiency. Insulin resistance is recognized as a core mechanism of hyperglycemia, hyperuricemia, and dyslipidemia [18]. An increased level of PRL may be associated with increased tissue resistance to insulin [19]. However, in this patient, the improvement in HOMA-IR following normalization of PRL levels was modest, which may be related to factors such as lifestyle and genetic predisposition. The elevated lipoprotein(a) level is notable, as it is an established independent risk factor for (ASCVD) [20]. Therefore, regular lipid monitoring and cardiovascular risk assessment are warranted in this patient. Of further note, a mismatch between height and weight Z-scores has been observed in a subset of adult patients with WSS, suggesting an increased tendency toward overweight or obesity [8]. In the present case, limited sun exposure likely contributed to vitamin D deficiency, and increased outdoor activity may help improve both vitamin D status and insulin resistance.

Management of WSS should encompass the entire lifespan, although treatment priorities differ between children and adults [13]. Currently, management remains largely symptomatic. Children with WSS are more commonly referred to endocrinology services due to short stature, given the emphasis on linear growth during this period; growth hormone deficiency (GHD) has been reported in 18.8–50.0% of pediatric cases [6]. Recombinant human growth hormone therapy help these children achieve satisfactory adult height, and no adverse effects have been reported to date [6, 21]. In contrast, adults with WSS face greater challenges related to mental health and social integration. For those receiving antipsychotic treatment, careful monitoring for potential side effects is essential. Educational attainment, daytime activities, and employment status vary considerably among affected adults, and individuals who are unemployed or have limited education may require additional support from family and society [9, 13].

In conclusion, clinicians should be aware of the risk of antipsychotic-induced hyperprolactinemia in patients with WSS, given the high prevalence of mental health conditions in this population. Metabolic disorders, hyperandrogenemia, and menstrual disorders are also common endocrine concerns that warrant attention. Endocrine surveillance and clinical management should extend throughout adulthood and across the entire lifespan in individuals with WSS.

Abbreviations

ASCVD

Atherosclerotic cardiovascular disease

β-CTX

C-terminal cross-linking telopeptide of type I collagen

BMD

Bone mineral density

BMI

Body mass index

BMP

Bone morphogenetic protein

DHEA-S

Dehydroepiandrosterone sulfate

eNOS

Endothelial nitric oxide

FCP

Fasting C-peptide

FINS

Fasting insulin

FPG

Fasting plasma glucose

GHD

Growth hormone deficiency

HbA1c

Glycated hemoglobin A1c

HOMA

Homeostasis model assessment

HOMA-IR

HOMA-insulin resistance

IGT

Impaired glucose tolerance

KMT2A

Lysine-specific methyltransferase 2 A

MRI

Magnetic resonance imaging

PCOS

Polycystic ovary syndrome

OGTT

Oral glucose tolerance test

PRL

Prolactin

PTH

Parathyroid hormone

P1NP

Procollagen type 1 N-terminal pro-peptide

SAHZU

Second Affiliated Hospital, Zhejiang University School of Medicine

T25OHD

Total 25-hydroxy vitamin D

UA

Uric acid

WES

Whole-exome sequencing

WNT

Wingless/Int-1

WSS

Wiedemann-Steiner syndrome

2hCP

2-hour postprandial C-peptide

2hINS

2-hour postprandial insulin

2hPG

2-hour postprandial plasma glucose

Author contributions

HT Liang, J Kong, and XH Xu collected clinical information of the patient. HT Liang, J Kong, and X Li collected the blood samples and analyzed the genetic results. HT Liang and J Kong wrote the manuscript. XH Xu and C Zheng revised the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the Natural Science Foundation of Zhejiang Province (LQ23H070003) and the Medical and Health Science and Technology Planning Project of the Zhejiang Province (2023RC167).

Data availability

The raw datasets generated and/or analyzed during this study have been deposited in the ClinVAR database, under accession number SCV006099292.

Declarations

Ethics approval and consent to participate

This study was performed with the approval of the Ethics Committee of The Second Affiliated Hospital, Zhejiang University School of Medicine (SAHZU) (2022-0056). Written informed consent was obtained from the individual and family members.

Consent for publication

Written informed consent was obtained from the patient and her parents for publication of any potentially identifiable images or data included in this case report.

Competing interests

The authors declare no competing interests.