Wolman disease revealed by fetal adrenal calcifications: a case report

¹Regional Hospital of Menzel Temim, Department of Gynecology and Obstetrics, 8080, Menzel Temim, Nabeul, Tunisia

^&Corresponding author
Aymen Khalfaoui, Regional Hospital of Menzel Temim, Department of Gynecology and Obstetrics, 8080, Menzel Temim, Nabeul, Tunisia

Introduction    

Wolman disease is a rare and severe autosomal recessive lysosomal storage disorder caused by mutations in the LIPA gene, resulting in a deficiency of lysosomal acid lipase (LAL) [1]. This enzyme deficiency leads to the pathological accumulation of cholesteryl esters and triglycerides in multiple organs, including the liver, spleen, and adrenal glands, ultimately causing hepatosplenomegaly, adrenal calcifications, malabsorption, and multi-organ failure [2]. The condition typically manifests in the first months of life and is rapidly fatal without enzyme replacement therapy [1]. Early diagnosis is essential for timely genetic counseling and management decisions, especially in high-risk populations such as consanguineous couples [3]. Although postnatal diagnosis is more common, prenatal detection remains rare, but it can be life-saving by guiding clinical decisions [3]. We report a case of Wolman disease diagnosed prenatally in a fetus with multiple ultrasound abnormalities in a consanguineous couple.

Patient and observation     

Patient information: we report the case of a 28-year-old woman, blood type A-positive, with no significant medical history, in her first pregnancy (gravida 1, para 0, abortus 0). The pregnancy was spontaneous and unmonitored until 18 weeks of gestation. The patient was in a consanguineous marriage, and there was no known family history of genetic or metabolic disorders. She was referred to our department due to suspicion of a polymalformative syndrome detected during a routine prenatal ultrasound.

Timeline of the current episode: at 18 weeks of gestation, a routine ultrasound identified multiple fetal anomalies. At 19 weeks, a detailed morphological ultrasound confirmed central nervous system anomalies, hepatosplenomegaly, adrenal calcifications, and intrauterine growth restriction (IUGR). At 20 weeks, an amniocentesis was performed to investigate a possible genetic or metabolic etiology. By 21 weeks, enzymatic testing confirmed absence of lysosomal acid lipase (LAL) activity, consistent with a diagnosis of Wolman disease. At 22 weeks, a multidisciplinary counseling session was held with the parents, and at 23 weeks, medical termination of pregnancy was performed following the parents´ decision.

Clinical findings: ultrasound examination revealed hepatosplenomegaly (Figure 1) and bilateral adrenal calcifications (Figure 2). Central nervous system anomalies included cerebellar hypoplasia (Figure 3), microcephaly and ventriculomegaly (Figure 4), as well as agenesis of the corpus callosum. Additional abnormalities such as hyperechoic intestines (Figure 1) and severe intrauterine growth restriction were also noted. This polymalformative pattern raised a strong suspicion of an underlying genetic or metabolic disorder.

Diagnostic assessment: a metabolic or genetic disorder was suspected based on the ultrasound findings. Amniocentesis was performed at 20 weeks of gestation and revealed absent LAL enzymatic activity, confirming the diagnosis of Wolman disease. Fetal karyotype analysis returned normal, excluding chromosomal abnormalities. The constellation of imaging findings further supported the diagnosis. No specific diagnostic challenges were encountered during testing.

Diagnosis: the final diagnosis was Wolman disease, a rare autosomal recessive lysosomal storage disorder caused by LIPA gene mutations leading to LAL deficiency and lipid accumulation in multiple organs. The prognosis was extremely poor in the absence of enzyme replacement therapy (ERT), with survival typically limited to the first year of life.

Therapeutic interventions: after extensive counseling, the parents opted for medical termination of pregnancy due to the uniformly poor prognosis. The procedure was carried out at 23 weeks of gestation using misoprostol (cytotec), following the FIGO protocol. Delivery resulted in a stillborn female fetus with no visible external malformations.

Follow-up and outcome of interventions: post-termination fetopathological examination confirmed the prenatal findings, including hepatosplenomegaly (Figure 5), microcephaly, cerebellar hypoplasia, ventriculomegaly, agenesis of the corpus callosum, and adrenal calcifications (Figure 6). These findings were consistent with a diagnosis of Wolman disease. No maternal complications were reported following the procedure.

Patient perspective: while a direct patient perspective was not obtained due to the nature of the case, the parents expressed deep emotional distress along with appreciation for the timely and accurate prenatal diagnosis. They acknowledged the value of genetic counseling and expressed hope that early screening could help avoid similar tragedies in future pregnancies.

Informed consent: written informed consent was obtained from the patient for publication of this case report and any associated images.

Discussion     

Wolman disease is a rare and severe lysosomal storage disorder caused by a deficiency in lysosomal acid lipase (LAL), an enzyme essential for the breakdown of cholesterol esters and triglycerides within lysosomes. This deficiency leads to the pathological accumulation of lipids in multiple organs, including the liver, spleen, adrenal glands, and intestines, resulting in progressive multi-organ dysfunction [2]. Traditionally, Wolman disease has been diagnosed postnatally based on clinical symptoms such as hepatosplenomegaly, adrenal calcifications, and failure to thrive, often leading to death within the first year of life if untreated [4]. However, advances in prenatal diagnostics, including imaging and enzymatic assays, now allow for earlier detection, which is critical for family counseling and therapeutic planning [3]. In this case, prenatal ultrasound findings-such as hepatosplenomegaly, adrenal calcifications, and intrauterine growth restriction (IUGR)-raised suspicion of Wolman disease. These features, although nonspecific, are highly suggestive of lysosomal storage disorders and prompted further diagnostic evaluation. The absence of LAL activity, confirmed through enzymatic assays, provided a definitive diagnosis, enabling the parents to make an informed decision regarding pregnancy management [5]. This case underscores the importance of integrating detailed prenatal imaging with biochemical and genetic testing to identify rare metabolic disorders early in gestation.

Historically, Wolman disease carried a grim prognosis, with most affected infants succumbing to multi-organ failure within the first year of life [6]. However, the introduction of enzyme replacement therapy (ERT) with sebelipase alfa has revolutionized the management of this condition. Sebelipase alfa, a recombinant form of LAL, has been shown to improve survival, reduce lipid accumulation, and enhance quality of life in affected individuals [7]. Early initiation of ERT, ideally within the first weeks of life, is critical to slowing disease progression and preventing irreversible organ damage [8]. This highlights the importance of prenatal diagnosis, as it allows for timely intervention and improves the likelihood of favorable outcomes. Despite these advancements, significant challenges remain in the diagnosis and management of Wolman disease. First, the condition is not routinely included in standard prenatal screening panels, making it reliant on clinical suspicion and targeted testing [9]. Additionally, the early imaging features of Wolman disease, such as hepatosplenomegaly and adrenal calcifications, can overlap with other metabolic or hematologic disorders, complicating the diagnostic process [10]. Furthermore, while ERT has transformed the natural history of Wolman disease, its efficacy depends on the timing of treatment initiation and the extent of organ damage at birth. Infants with advanced disease at the time of diagnosis may still experience significant morbidity despite therapy [1].

Future research should prioritize several key areas to enhance outcomes for patients with Wolman disease. First, improving prenatal screening methods-such as integrating LAL activity assays into routine testing-could enable earlier diagnosis and intervention [9]. Second, investigating potential in utero treatments, including gene therapy or intrauterine enzyme replacement therapy (ERT), may help prevent or reduce organ damage before birth [6]. Lastly, continued advancements in novel therapies, such as gene editing and stem cell-based approaches, offer promising prospects for correcting the underlying genetic defect and providing long-term solutions for affected individuals [1].We should keep in mind the existence of other diseases causing adrenal calcifications such as Congenital adrenal hyperplasia with 21-hydroxylase deficiency, cerebrotendinous xanthomatosis, congenital infections (TORCH: toxoplasmosis, rubella, cytomegalovirus, herpes).

Wolman disease represents a devastating but increasingly manageable lysosomal storage disorder. Prenatal diagnosis, facilitated by advances in imaging and biochemical testing, plays a pivotal role in enabling early intervention and improving outcomes. While ERT has significantly altered the prognosis of this condition, challenges remain in ensuring timely diagnosis and optimizing long-term management. Continued research and innovation in prenatal screening, in utero therapies, and novel treatment modalities are essential to further improving the lives of patients with Wolman disease.

Conclusion     

This case reports the prenatal diagnosis of Wolman disease in a fetus with multiple malformations including hepatosplenomegaly, adrenal calcifications, and central nervous system anomalies. It highlights that prenatal identification of Wolman disease is achievable through detailed imaging and enzymatic testing, particularly in high-risk cases such as consanguineous pregnancies. The key takeaway is the importance of early and accurate prenatal diagnosis to guide parental decision-making and genetic counseling, which can significantly impact the management of future pregnancies.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Patient management: Houssem Ragmoun, Amina Abaab, and Montacer Hafsi. Data collection: Sarra Rihani, Mariem Bezzine, Kristou Eya, and Aida Masmoudi. Ultrasound imaging and interpretation: Kristou Eya and Aida Masmoudi. Manuscript drafting: Aymen Khalfaoui and Sarra Rihani. Manuscript revision and final approval: Houssem Ragmoun, Amina Abaab, Montacer Hafsi, Sarra Rihani, Mariem Bezzine, Kristou Eya, Aida Masmoudi. All the authors have read and agreed to the final manuscript.

Figures     

Figure 1: prenatal ultrasound showing fetal hepatosplenomegaly(star) and hyperechoic intestine (arrow)

Figure 2: prenatal ultrasound showing adrenal calcifications (arrow)

Figure 3: cerebellar hypoplasia (arrow)

Figure 4: ventriculomegaly (star) and microcephaly (arrow)

Figure 5: fetopathological examination showing hepatosplenomegaly (star)

Figure 6: fetopathological examination showing adrenal calcifications (arrow)

References