Diets-Jongmans Syndrome due to a Novel KDM3B Variant: The First Molecularly Confirmed Case from Turkey

Abstract

Introduction

Diets-Jongmans syndrome (DIJOS) is a rare neurodevelopmental disorder associated with heterozygous variants in KDM3B. The phenotypic spectrum continues to expand as additional individuals are identified.

Case Presentation

We report an 8-year-old girl who presented with short stature, micrognathia, a pointed chin, and mild developmental delay. Exome sequencing revealed a novel likely pathogenic heterozygous nonsense variant, KDM3B (NM_016604.4)c.5068C>T p.(Gln1690Ter), which was also detected in her mother. Biochemical evaluation revealed growth hormone deficiency, which was confirmed by two stimulation tests. Short stature without intellectual disability was noted in the mother, indicating intrafamilial phenotypic variability.

Conclusion

This case represents the first molecularly confirmed DIJOS patient from Turkey and adds further clinical observations regarding growth hormone deficiency in a patient with DIJOS.

Established Facts

• Diets-Jongmans syndrome is a rare neurodevelopmental disorder caused by heterozygous pathogenic variants in KDM3B.

• The phenotypes commonly include developmental delay, distinctive craniofacial features, feeding difficulties, and intellectual disability.

• Variable expressivity has been reported among affected individuals.

Novel Insights

• This report documents the first molecularly confirmed case of Diets-Jongmans syndrome from Turkey.

• The patient exhibited biochemically confirmed growth hormone deficiency, which may represent an associated or incidental finding in KDM3B-related disease.

• Marked intrafamilial variability was observed: the patient’s mother carried the same variant but showed only short stature without neurocognitive impairment.

Introduction

KDM3B is located on chromosome 5q31 and encodes a histone H3 lysine 9 H3K9 demethylase that plays a crucial role in the epigenetic regulation of gene expression and chromatin remodeling [1]. Loss-of-function variants in KDM3B lead to haploinsufficiency and constitute the established molecular mechanism underlying Diets-Jongmans syndrome (DIJOS), an autosomal dominant neurodevelopmental disorder characterized by mild to moderate intellectual disability or developmental delay, short stature, feeding difficulties, and distinctive craniofacial features [2, 3]. The syndrome was first described by Diets et al. [3] in 2019, and to date, fewer than 30 affected individuals have been reported worldwide, highlighting the rarity and emerging nature of this condition. In this article, we present the first molecularly confirmed case of DIJOS from Turkey in an 8-year-old girl presenting with syndromic short stature and distinctive craniofacial features.

Case Report

An 8-year-old female patient presented to the pediatric endocrinology outpatient clinic with complaints of short stature. Her medical history revealed a birth weight of 2,600 g at term, and there was no notable prenatal history. There was no consanguinity between the parents. The patient had been poorly fed since infancy, and her height and weight had always been behind those of her peers. The patient’s anthropometric measurements were as follows: weight 15.4 kg (standard deviation score [SDS]: −3.27, percentile: 0.05, weight age: 3.65), height 107.8 cm (SDS: −3.41, percentile: 0.03, height age: 4.8), BMI 13.25 kg/m² (SDS: −1.73, percentile: 4.18), head circumference 46 cm (SDS: −3.96, percentile: <0.02), and arm span 105 cm. The midparental target height was calculated as 145 cm (−3.08 SDS, 0.1 percentile). SDSs were calculated according to the Neyzi et al. [4] growth standards for Turkish children. Pubertal examination revealed thelarche and pubarche stage 1 and no axillary hair. Physical examination revealed a pointed chin, micrognathia, and a wide nasal tip (Fig. 1). Neurodevelopmental evaluation was performed by the Child Psychiatry and Child Development units using the Denver II Developmental Screening Test on two occasions, at 4 years and 5 months and again at 4 years and 9 months. Both assessments yielded abnormal results, with delays documented across all developmental domains, including personal-social, fine motor-adaptive, language, and gross motor areas. In the language domain, the patient had a limited expressive vocabulary of approximately 10 single words, difficulty answering questions, and poor speech intelligibility. Fine motor deficits included weak pencil grasp, inability to copy a circle or construct a bridge model, and difficulty distinguishing long and short lines. In the gross motor domain, she was unable to hop on one foot and could maintain single-leg stance for only 3–4 s. Based on these findings, preschool attendance and special education support were recommended. Initial investigations for short stature revealed normal complete blood counts, renal and liver function tests, and anterior pituitary hormone levels. The patient’s bone age was compatible with that at 6 years, her IGF-1 level was 90 ng/mL (−1.38 SDS), and her IGFBP-3 level was 4,600 ng/mL (−0.9 SDS). Celiac disease tests were negative. An echocardiogram performed due to growth retardation revealed no pathological findings. Owing to marked short stature (height SDS <−2) and insufficient growth velocity, two growth hormone (GH) stimulation tests were performed, which showed inadequate peak responses (first test: 1.97 μg/L; second test: 1.36 μg/L), which was consistent with GH deficiency. The decision regarding GH therapy will be made during follow-up.

Fig. 1.

Facial features of the patient demonstrating micrognathia, a pointed chin, and a wide nasal tip.

Considering the short stature along with mild intellectual disability and distinctive craniofacial features, the patient was referred to the pediatric genetics department with a preliminary diagnosis of syndromic short stature, and molecular analysis was planned. Chromosome analysis for chromosomal disorders revealed a normal karyotype, and microdeletion analysis revealed no pathological copy number changes (Tables 1, 2).

Table 1.

Comparison of phenotypic features of our patient with previously reported DIJOS cases

Feature	Our case	Diets et al. [3]	Tabaku et al. [5]	Zhao et al. [6]
Short stature	+	+	+	+
Height SDS	−3.41	−2.0 to −4.5	−3.1	−3.4
Intellectual disability	Mild	Mild-moderate	Significant	Significant
Feeding difficulties	+	+	+	+
Distinctive craniofacial features	Pointed chin, wide nasal tip, micrognathia	Broad mouth, pointed chin, long ears, wide nasal tip	Broad mouth, long ears	Pointed chin, wide nasal tip
GH deficiency	+	Not reported	−	−
Familial segregation (mother)	+	+ (reported in some cases)	−	−

+, present; −, absent; SDS, standard deviation score.

Table 2.

Summary of published cases of DIJOS

Publication/case	Genetic variant	Main clinical features	Additional findings
Diets et al. [3] (17 cases)	De novo/familial KDM3B mutations	Intellectual disability, short stature, characteristic distinctive craniofacial features (broad mouth, pointed chin, long ears)	Behavioral problems, feeding difficulties, seizures in some patients, cardiac/renal anomalies
Tabaku et al. [5] (1 case)	De novo frameshift mutation	Motor and speech delay, short stature, long ears, broad mouth	Feeding difficulties, vomiting, dental issues
Zhao et al. [6] (2 cases)	Case 1: splice-site c.5070+1G>A	Intellectual disability, short stature, distinctive craniofacial features	Case 1: transient neutropenia
	Case 2: missense p.R943Q		Case 2: cardiomyopathy, edema, upper respiratory tract infections

Genetic Analysis

Exome sequencing (ES) was performed on an Illumina NextSeq 500 platform via the Agilent SureSelect Human All Exon V7 capture kit. Sequencing achieved a mean coverage of approximately 120×, with more than 98% of the target regions covered at a minimum depth of 20×. Genomic DNA was extracted from peripheral blood leukocytes, and bioinformatic analysis focused on rare variants with a minor allele frequency <0.01 in population databases (gnomAD), prioritizing protein-altering variants consistent with an autosomal dominant inheritance model. Variant interpretation was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines [7]. Variant nomenclature is reported according to HGVS recommendations [8]. A novel heterozygous nonsense variant, KDM3B (NM_016604.4)c.5068C>T p.(Gln1690Ter), was identified and considered causative for the patient’s phenotype [2]. The variant was absent from population databases, including gnomAD [9], and was not listed in ClinVar at the time of analysis [10]. The submission process to ClinVar is currently in progress. The variant was classified as likely pathogenic on the basis of the ACMG criteria (PVS1 and PM2) [7]. As no functional studies have been performed, haploinsufficiency is considered a likely but unproven disease mechanism based on the predicted loss-of-function effect of the variant.

Segregation analysis was performed using ES data obtained from the mother, which revealed the same heterozygous variant. She had a head circumference of 52.5 cm (approximately −1.6 SDS) and short stature (height: 143 cm, −3.42 SDS). She was clinically evaluated by pediatric genetics and pediatric endocrinology specialists and had normal cognitive function. She had completed secondary education and reported no learning difficulties, supporting intrafamilial phenotypic variability. She shares similar distinctive craniofacial features with her daughter, including a pointed chin and a wide nasal tip. Sanger sequencing was not performed for orthogonal confirmation of the variant, which represents a methodological limitation of this single-family case report.

Discussion

DIJOS is a recently described neurodevelopmental disorder caused by heterozygous pathogenic variants in KDM3B, which encodes a histone demethylase involved in transcriptional regulation [3]. To date, fewer than 30 affected individuals have been reported, and the phenotypic spectrum continues to expand as additional cases are described. Common clinical features include developmental delay, mild to moderate intellectual disability, short stature, feeding difficulties, and distinctive craniofacial features.

Consistent with previous reports, our patient presented with short stature, feeding difficulties, expressive language delay, and mild intellectual disability, along with typical facial features such as a pointed chin and a wide nasal tip [3]. Notably, the patient’s mother carried the same pathogenic KDM3B variant but exhibited only isolated short stature without neurocognitive impairment, highlighting marked intrafamilial phenotypic variability. Variable expression has been recognized as a characteristic feature of KDM3B-related disorders, suggesting that additional genetic, epigenetic, or environmental modifiers may influence phenotypic severity [3].

Several additional clinical manifestations have been reported in isolated cases, further underscoring the heterogeneity of this syndrome. A de novo pathogenic KDM3B variant was identified in the first reported Albanian case of DIJOS, with clinical features largely overlapping those previously described [5]. In another report, a KDM3B variant co-occurred with a pathogenic variant in SIN3A, and the patient presented with interstitial lung disease and pulmonary arterial hypertension [11]. Furthermore, two patients with KDM3B variants were described with novel clinical findings, including transient neutropenia and cardiomyopathy [6]. In contrast, no pulmonary, cardiac, or hematologic abnormalities were detected in our patient.

Short stature is a frequent but nonspecific finding in DIJOS; however, biochemically confirmed GH deficiency has rarely been reported. Only a limited number of cases in the literature have documented GH deficiency, and data regarding GH therapy remain scarce [5]. In our patient, GH deficiency was confirmed by insufficient responses to two GH stimulation tests. Given the role of KDM3B in epigenetic regulation, a loss-of-function effect could theoretically influence hypothalamic-pituitary axis development; however, current evidence is insufficient to establish a direct causal relationship. Accordingly, GH deficiency should be regarded as a possible associated finding rather than a defining feature of DIJOS until further cases are reported. A potential association between KDM3B variants and hematologic malignancies has also been suggested. Experimental studies have implicated KDM3B in the transcriptional regulation of genes involved in hematopoiesis and leukemogenesis [2]. Clinically, leukemia and lymphoma have been reported in a small number of patients with KDM3B variants [3]. However, the limited number of reported cases precludes definitive conclusions regarding increased malignancy risk. On the basis of currently available evidence, routine malignancy screening beyond standard pediatric follow-up is not recommended, although clinicians should remain aware of this possible association.

In conclusion, this case provides additional clinical observations regarding GH deficiency as a possible associated finding in a patient with DIJOS. The presence of the same variant in the patient’s mother, who exhibited isolated short stature without neurocognitive impairment, emphasizes pronounced intrafamilial variability and supports the concept of variable expressivity in KDM3B-related disorders. These findings highlight the importance of comprehensive endocrine and genetic evaluation in children presenting with syndromic short stature and suggest that GH deficiency may represent an underrecognized feature of this emerging syndrome.

A limitation of this report is the absence of formal quantitative IQ testing, as neurocognitive assessment relied primarily on repeated Denver II screening evaluations and detailed clinical developmental examinations. Nevertheless, consistent multi-domain delays documented longitudinally provide objective support for neurodevelopmental impairment. Another limitation is that the identified KDM3B variant was not independently confirmed by Sanger sequencing, and segregation relied solely on ES data.

Conclusions

We report the first molecularly confirmed case of DIJOS from Turkey associated with biochemically proven GH deficiency. This case provides further observations regarding GH deficiency as a possible associated finding in KDM3B-related disease and highlights marked intrafamilial phenotypic variability. Our findings emphasize the importance of considering rare genetic syndromes in children presenting with syndromic short stature and support the role of comprehensive genetic and endocrine evaluation in establishing an accurate diagnosis.

Statement of Ethics

Written informed consent was obtained from the patient’s parents for participation in the study and for publication of clinical details and accompanying images. According to national regulations, case reports do not require formal Ethics Committee approval. The CARE checklist has been completed and is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550846).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

D.D.: conceptualization, clinical evaluation, genetic interpretation, and manuscript writing. A.G.: clinical assessment and data collection. E.K.: genetic counseling and manuscript review. D.T.: phenotypic assessment and literature review. P.K.: endocrine evaluation and GH stimulation testing. All the authors approved the final manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All the data generated or analyzed during this study are included in this article and its online supplementary material. Additional details are available from the corresponding author upon reasonable request.