Jacobsen Syndrome: A Case Report With Olfactory Bulb Agenesis, Severe Endocrinopathy, and Neurodevelopmental Delay

ABSTRACT

Jacobsen syndrome is a rare 11q deletion disorder with multisystem involvement. This case highlights a complex unbalanced 11;15 translocation, olfactory bulb agenesis, extensive white matter abnormalities, and severe endocrinopathies, emphasizing the need for comprehensive genetic and neuroimaging evaluations.

1. Introduction

Jacobsen syndrome (JS), also known as 11q terminal deletion disorder, is a rare chromosomal disorder resulting from a partial deletion of the long arm of chromosome 11 (11q). First described by Petrea Jacobsen in 1973, the syndrome presents with a broad spectrum of clinical manifestations affecting multiple organ systems [1]. The genetic basis of JS lies in the loss of multiple contiguous genes within the distal 11q region, typically ranging from 7 to 20 Mb, although smaller interstitial deletions have also been documented [2]. Clinically, JS is characterized by a distinct craniofacial phenotype, congenital heart anomalies, developmental delays, hematological abnormalities, and immune dysfunction. Dysmorphic features commonly observed in affected individuals include hypertelorism, epicanthal folds, a high forehead, trigonocephaly, and a broad nasal bridge [3]. Neurodevelopmental impairment is nearly universal, manifesting as global developmental delays, intellectual disability, and speech impairments, with a subset of individuals meeting diagnostic criteria for autism spectrum disorder [2]. Hematological complications arise primarily from Paris‐Trousseau syndrome, a congenital thrombocytopenia with functional platelet defects, leading to an increased risk of bleeding and intracranial hemorrhages [4]. Congenital heart defects, including ventricular septal defects, hypoplastic left heart syndrome, and valvular abnormalities, are among the most life‐threatening features of the disorder [3]. Endocrine dysfunction is also commonly reported, with short stature, growth hormone deficiency, and hypothyroidism being frequent findings in affected individuals [1]. Additionally, JS is increasingly recognized as a disorder associated with immune deficiency, with patients exhibiting hypogammaglobulinemia, recurrent infections, and defects in both T and B lymphocyte populations [1].

While many of these features have been well documented in the literature, novel findings continue to expand the phenotypic spectrum of JS. This report presents a unique case of Jacobsen syndrome with an unbalanced translocation involving chromosomes 11 and 15, a rare genetic event with limited documentation in medical literature. In addition to classical phenotypic features, this case is notable for its previously unreported combination of neurodevelopmental delay, absent olfactory bulb, white matter abnormalities on MRI, and multiple endocrinopathies, highlighting the importance of comprehensive neuroimaging and genetic characterization in individuals with atypical presentations.

Here, we present a rare and atypical case of Jacobsen syndrome involving an unbalanced translocation between chromosomes 11 and 15, broadening the clinical and genetic spectrum of the disorder.

2. Case Presentation

A 7‐month‐old male presented with concerns of developmental delay, hypotonia, and poor growth noted since birth. The patient was evaluated and treated at a tertiary pediatric center in the United States, where multidisciplinary services were available. His mother reported delayed motor milestones, including poor head control beyond 4 months of age and an inability to sit with support at the time of evaluation. She also reported dysmorphic features and feeding difficulties, prompting a comprehensive evaluation.

The patient was born at 38 + 6 weeks via C‐section due to prenatal detection of craniofacial abnormalities. Birth weight was 3.255 kg (7 lb. 2.8 oz), and Apgar scores were 8 at 1 and 5 min. Postnatally, he required a 26‐day stay in the neonatal intensive care unit (NICU) for respiratory distress and congenital anomalies. During this time, he was managed with non‐invasive respiratory support, including nasal continuous positive airway pressure for the first 5 days of life, followed by high‐flow nasal cannula for an additional 4 days. He was weaned to room air by day 10 of life and remained stable off respiratory support for the remainder of the NICU course. He was discharged home on room air without supplemental oxygen or respiratory devices.

Family history was negative for known genetic disorders, but genetic analysis later identified a balanced translocation in the father. On the examination when the patient was at 7 months of age, the patient exhibited microcephaly, periorbital hyperpigmentation, overlapping fingers, and hypotonia. The neurological evaluation confirmed global developmental delay, with deficits observed across all major developmental domains. Gross motor delays included poor head control beyond 4 months, inability to roll over, and lack of trunk stability. Fine motor skills were also significantly delayed, with minimal reaching behavior appropriate for age. Language development was limited to cooing sounds without response to name. Social–emotional delays included poor eye contact and reduced interaction with caregivers. The endocrine assessment identified hypothyroidism and growth hormone deficiency.

2.1. Diagnostic Evaluation

Neuroimaging and genetic analysis were conducted at the age of 7 months to further evaluate the patient's developmental delays and dysmorphic features. Brain MRI findings revealed significant structural abnormalities (Figures 1 and 2), including the absence of the right olfactory bulb, which may contribute to anosmia or olfactory dysfunction. Additionally, there was hypoplasia of the sella turcica, suggesting potential pituitary involvement, which correlates with the patient's diagnosed growth hormone deficiency. Furthermore, T2 FLAIR sequences demonstrated confluent and patchy hyperintensities located in the periventricular and subcortical white matter of the bilateral frontal, parietal, and left greater than right temporal regions. These hyperintensities indicate potential leukoencephalopathy or delayed myelination, which may explain the patient's hypotonia and global developmental delay. In addition, a renal ultrasound was performed and showed no abnormalities.

FIGURE 1.

Brain MRI Findings. (A) Coronal T2‐weighted MRI demonstrating asymmetry of the olfactory bulbs, with a normal left olfactory bulb (arrow) and complete absence of the right olfactory bulb (arrowhead). This finding suggests olfactory bulb agenesis, a rare neurodevelopmental anomaly not typically associated with Jacobsen syndrome. (B) Sagittal T1‐weighted MRI showing a hypoplastic sella turcica (arrow), which is indicative of pituitary dysgenesis.

FIGURE 2.

Axial Brain MRI. (A) Axial T2‐FLAIR MRI showing confluent and patchy hyperintensities in the periventricular and subcortical white matter of the bilateral frontal and parietal lobes. These findings suggest delayed myelination or leukoencephalopathy, which may contribute to the patient's global developmental delay and hypotonia. The enlarged lateral ventricles may indicate mild ventriculomegaly, raising concerns about possible impaired cerebrospinal fluid dynamics. (B) Axial T2‐FLAIR MRI at the level of the brainstem demonstrating small nonspecific white matter abnormalities and small cystic changes within the temporal lobes. 

Genetic testing confirmed a 13,815 kbp deletion on chromosome 11q23.3–q25, a well‐characterized deletion associated with Jacobsen syndrome, impacting multiple developmental and neurological pathways. Additionally, there was a 9550 kbp duplication at chromosome 15q26.1–q26.3, which may further contribute to the patient's growth abnormalities and endocrine dysfunction. The cytogenetic analysis identified an unbalanced translocation, 46, XY, der (11) t (11;15) (q23.3; q26.1) pat, inherited from the father, confirming a complex chromosomal rearrangement. This finding is significant as it suggests a familial component to the chromosomal alteration, warranting genetic counseling for the family.

2.2. Management and Follow‐Up

Given the presence of multiple endocrinopathies, the patient was initiated on hormonal therapy to address his underlying deficiencies. He was prescribed levothyroxine (37.5 mcg daily) for hypothyroidism to support normal thyroid function and metabolism. Additionally, due to growth hormone deficiency, he was started on Omnitrope (growth hormone) at a dosage of 0.6 mg nightly (0.185 mg/kg/week) to promote linear growth and improve overall metabolic function. These therapies were initiated in the outpatient setting, and the patient did not require hospitalization during the course of medical management. A multidisciplinary care plan was implemented to comprehensively address the patient's complex medical needs. His management involved pediatric endocrinology, neurology, cardiology, and therapy services, ensuring coordinated care across multiple specialties. Due to congenital heart concerns, a cardiology procedure has been scheduled for February 2024 to assess and manage potential structural or functional abnormalities of the heart.

At follow‐up, the patient demonstrated notable improvements in strength, balance, feeding ability, and growth following hormone therapy. His mother reported a flu episode in December 2024, but he recovered without complications, suggesting a stable immune response despite his underlying condition. He continues to receive speech, occupational, and physical therapy, which have contributed to gradual developmental progress. These interventions have played a crucial role in supporting his motor skills, cognitive development, and overall quality of life.

Long‐term monitoring remains essential to evaluate the patient's response to therapy, ensure appropriate growth and metabolic regulation, and address any emerging medical concerns. Future evaluations will include serial endocrinologic assessments, neurological follow‐up, and cardiac monitoring to optimize his long‐term outcomes.

3. Discussion

JS is a rare chromosomal disorder caused by deletions in the distal long arm of chromosome 11 (11q). While the classical phenotype includes developmental delay, congenital heart defects, thrombocytopenia, and immune dysfunction [1, 2, 3, 4]. The case presented here is particularly unique due to the presence of an unbalanced translocation involving chromosomes 11 and 15, olfactory bulb agenesis, extensive white matter abnormalities on MRI, and severe endocrine dysfunction. These findings suggest an expanded phenotypic spectrum of JS, reinforcing the role of advanced genetic and neuroimaging assessments in the diagnosis and management of atypical presentations.

This case underscores the complex genetic landscape of Jacobsen syndrome, with a confirmed 13,815 kbp deletion on chromosome 11q23.3–q25, a well‐characterized pathogenic deletion associated with JS, alongside a 9550 kbp duplication at chromosome 15q26.1–q26.3. The presence of a paternal unbalanced translocation, 46, XY, der (11) t (11;15) (q23.3;q26.1)pat, suggests a familial inheritance pattern, emphasizing the importance of genetic counseling for affected families.

While 11q deletions have been well documented, the additional duplication on 15q26.1–q26.3 introduces an unexplored genetic variable, potentially exacerbating the patient's phenotype. Chromosome 15q duplications have been linked to growth abnormalities, neurodevelopmental disorders, and endocrine dysfunction, aligning with the clinical findings in this case [5]. The concurrent loss of function at 11q and gain of function at 15q could represent a double‐hit mechanism, intensifying the neurodevelopmental and endocrine manifestations observed in this patient [6, 7].

One of the most striking findings in this case is the absence of the right olfactory bulb, a feature that has not been widely described in JS. The olfactory bulb plays a critical role in sensory processing, and its agenesis may contribute to olfactory dysfunction or impaired sensory integration. Interestingly, in a study by Booth and Rollins (2016) [8], olfactory bulb agenesis was reported in a subset of patients with chromosomal disorders, including cases with 11q deletions, suggesting a possible link between olfactory anomalies and broader neurodevelopmental abnormalities. Their findings further support the hypothesis that early disruption of neural crest‐derived structures, including the olfactory system, may play a role in the sensory and cognitive deficits observed in Jacobsen syndrome. Additionally, the extensive white matter hyperintensities observed on MRI, particularly in the periventricular and subcortical regions, suggest dysregulated myelination or leukoencephalopathy, which may underlie the patient's hypotonia and global developmental delay. A study by Fujino et al. [9] identified white matter abnormalities in a patient with Jacobsen syndrome, which was associated with deletions in the HEPACAM/GlialCAM gene located at 11q, a gene known to play a role in glial cell adhesion and ion homeostasis. Their findings suggest that white matter changes in JS may be due to chronic white matter edema, resembling features of megalencephalic leukoencephalopathy with subcortical cysts type 2B. Notably, their study documented progressive improvement in myelination over time, an outcome that contrasts with the persistent white matter abnormalities observed in this case. This case also presents a severe endocrine phenotype, with both hypothyroidism and growth hormone deficiency (GHD). While GHD has been previously reported in JS, its pathogenesis remains poorly understood. The MRI finding of a hypoplastic sella turcica suggests pituitary dysgenesis, which could be a structural correlate for hypopituitarism. The association between JS and hypothalamic–pituitary dysfunction has been highlighted in a study by Pivnick et al. [10], where a patient with 11q23‐q25 deletion exhibited central hypothyroidism and partial growth hormone deficiency, indicating that the hypothalamic–pituitary axis is vulnerable to deletions within this region. Furthermore, Haghi et al. [11] reported that 50% of JS patients with short stature had low IGF‐1 levels, reinforcing the need for growth hormone axis evaluation in affected individuals. The presence of a 15q duplication in this case introduces an additional genetic factor, as this region has been associated with growth regulation and endocrine function.

The multisystemic complexity of this case highlights the importance of a multidisciplinary approach. The patient's notable response to growth hormone therapy, with improvements in strength, balance, and growth, underscores the benefit of early endocrine intervention. However, long‐term monitoring is crucial, as progressive neurological manifestations and immune dysfunction may emerge over time. Given the high risk of thrombocytopenia and bleeding complications in JS, periodic hematologic assessments are warranted, especially in light of the potential interplay between chromosomal abnormalities and platelet dysfunction. Goeller et al. [12] emphasize that Paris‐Trousseau syndrome, a highly penetrant platelet disorder in JS, predisposes patients to perioperative bleeding risks, necessitating preoperative hematology consultations and careful intraoperative management. Additionally, the presence of familial chromosomal rearrangement underscores the need for genetic counseling. While the father was asymptomatic, it remains possible that subclinical features or mosaicism could influence phenotypic expression. A study by Herrick et al. [13] demonstrated that patients with JS and additional chromosomal anomalies, such as unbalanced translocations, tend to have more severe congenital defects, particularly in the cardiac and immune systems. Families with a history of balanced translocations involving 11q may benefit from prenatal diagnostic strategies, including chromosomal microarray analysis and whole‐genome sequencing, to assess the risk of recurrence in future pregnancies.

4. Conclusion

This case underscores the need for individualized, multidisciplinary management in JS, integrating endocrinology, neurology, hematology, and genetic counseling to optimize long‐term outcomes. The patient's positive response to growth hormone therapy highlights the potential for early intervention to improve developmental trajectories. Longitudinal studies are necessary to assess the progression of white matter abnormalities in JS and their impact on neurodevelopmental outcomes. Additionally, investigations into the role of concurrent duplications (such as 15q26.1–q26.3) in phenotypic variability could provide deeper insights into the genetic mechanisms influencing severity in chromosomal disorders.

Author Contributions

Sajjad Ghanim Al‐Badri: conceptualization, writing – original draft. Aditya Duhan: data curation, writing – original draft. Rania H. Al‐Taie: writing – original draft. Muntadher Yousif Hasan Al Gehadi: writing – review and editing. Ibrahim Khalil: supervision, validation.

Consent

Written informed consent was obtained from the patient's legal guardians for the publication of this case report, including clinical details and imaging findings, while ensuring confidentiality and anonymity.

Conflicts of Interest

The authors declare no conflicts of interest.

Al‐Badri S. G., Duhan A., Al‐Taie R. H., Al Gehadi M. Y. H., and Khalil I., “Jacobsen Syndrome: A Case Report With Olfactory Bulb Agenesis, Severe Endocrinopathy, and Neurodevelopmental Delay,” Clinical Case Reports 13, no. 10 (2025): e71034, 10.1002/ccr3.71034.

Data Availability Statement

The data that support the findings of this study are included in the article.