Diets-Jongmans syndrome (DIJOS) is a recently described autosomal dominant condition caused by heterozygous pathogenic variants in the KDM3B gene. This syndrome is characterized by impaired intellectual development, short stature, and distinctive facial features.
Genetic Basis of Diets-Jongmans Syndrome
Diets-Jongmans syndrome (DIJOS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in the KDM3B gene, which is located on chromosome 5q31. The KDM3B gene encodes lysine-specific demethylase 3B, an enzyme involved in histone H3-K9 demethylation. This process is thought to control transcription through RNA polymerase II. The transmission pattern of DIJOS in some families is consistent with autosomal dominant inheritance. In other affected individuals, de novo occurrence has been confirmed.
In 2019, Diets et al. reported 17 patients with DIJOS, identifying 14 novel heterozygous mutations in the KDM3B gene. Four of these mutations were nonsense mutations, leading to the hypothesis that haploinsufficiency is the mechanism for the disorder. In 10 individuals, de novo occurrence was confirmed, and in 3, the mutations were inherited from a similarly affected parent. A case study described a new pediatric patient with a novel, heterozygous likely pathogenic variant in the KDM3B gene [c.305_315delinsTATGCT p.(Glu102Valfs*25)], which creates a shift in the reading frame starting at codon 102. This variant was not found in the patient's parents or in any of Diets' patient groups, indicating that it is a novel and de novo pathogenic variant in the KDM3B gene.
Clinical Characteristics
Diets et al. (2019) reported on 17 patients (9 males, 8 females) ranging in age from 9 months to 42 years with DIJOS. All affected individuals exhibited mild to moderate intellectual impairment.
Common Features
The majority of patients with DIJOS share a recognizable facial gestalt, including:
Read also: Diets of the Stars
- Long ears (present in 9 of 16 patients)
- Broad nasal tip (present in 14 of 16 patients)
- Thin upper vermilion (present in 12 of 16 patients)
- Wide mouth (present in 12 of 16 patients)
- Prominent or pointed chin (present in 13 of 16 patients)
Nonneutral palpebral fissures were also common, with 4 of 16 patients having upslanted and 5 of 16 having downslanted palpebral fissures. Ptosis and low columella were frequently reported.
Growth and Development
Short stature is a common feature of DIJOS. Nine of 16 patients were short, with a height below 2.5 SD, and two-thirds had a height below 1.5 SD. Many patients also experience developmental delays. A case study of an early childhood patient revealed delayed motor and speech development, as well as short stature and facial dysmorphism.
Behavioral and Neurological Issues
Behavioral problems, including ADHD and autism, were present in the majority (8 of 15) of patients. Two patients had both ADHD and autism. Three of 17 patients were reported with epilepsy, 4 of 17 with hearing loss, and 5 of 17 with childhood hypotonia.
Feeding Difficulties
Eight of 13 patients experienced neonatal feeding difficulties. One patient had feeding difficulties, started solid food at the age of five months with a lot of feeding difficulties with vomiting or spitting and till the age of seven months he did not accept any food other than breast milk which led to significant weight loss.
Other Clinical Manifestations
Other clinical manifestations reported in patients with DIJOS include:
Read also: Unpacking weird and dangerous diets
- Congenital diaphragmatic hernia (in 2 patients)
- Heterotaxy (in 1 patient)
- Strabismus (in 2 patients)
- Low vision and nystagmus (in 1 patient)
- Cryptorchidism
- congenital hypothyroidism
- hip dysplasia
Notably, two patients in the Diets et al. (2019) study had previously been reported in a cohort of children with cancer. One patient developed acute myeloid leukemia at age 14 and was born with congenital hypothyroidism and hip dysplasia. The other patient developed Hodgkin lymphoma at age 14 and also had umbilical and inguinal hernias and cryptorchidism.
Diagnosis
Because clinical genetic sequencing is widely used to diagnose individuals with unexplained neurodevelopmental problems, genetic testing is crucial for diagnosing DIJOS. Molecular genetic testing can identify heterozygous pathogenic variants in the KDM3B gene.
Differential Diagnosis
It is important to differentiate DIJOS from other syndromes with overlapping clinical features, such as other intellectual disability syndromes and conditions with similar facial dysmorphism.
Management
The management of DIJOS is multidisciplinary and focuses on addressing the various clinical manifestations of the syndrome. This may include:
- Developmental and educational support: Early intervention programs, speech therapy, occupational therapy, and special education services can help to maximize developmental potential and address learning difficulties.
- Behavioral management: Behavioral therapy, medication, and other interventions may be used to manage ADHD, autism, and other behavioral problems.
- Feeding support: Feeding therapy and nutritional support may be necessary to address feeding difficulties and ensure adequate growth.
- Medical management: Treatment for epilepsy, hearing loss, congenital heart defects, and other medical conditions may be required.
- Orthopedic management: Monitoring and treatment of hip dysplasia and scoliosis may be necessary.
- Monitoring for tumors: Given that 2 of the original patients reported by Diets et al. (2018) developed cancer, it is important to monitor patients and advice them to report any signs and symptoms to their doctor.
The Role of Sequencing Technology
This case also highlights the fact how sequencing technology has aided in finding a rising number of neurodevelopmental disorders (NDDs)-related genes.
Read also: Canine Gastroenteric Issues: A Diet Solution