Alagille syndrome (AS) or arteriohepatic dysplasia is a rare (1:30,000) autosomal-dominant inherited multisystem disorder [
15]. It primarily affects the liver, heart, eyes, face, skeleton, kidneys, and vascular system, whereas its expressivity (phenotypic severity) is highly variable, ranging from no apparent clinical involvement to severe disease that requires liver transplantation [
1,
8,
16,
19].
The occurrence of PTCS in AS is exceedingly rare [
9,
10,
20,
21]. Thus far ICP monitoring has not been reported in this subgroup of PTCS. Furthermore, owing to their rarity, the natural history and treatment of PTCS in AS patients remain unclear. Here, we present the clinical findings, ICP dynamics, and treatment outcome in a 4-yead-old boy with AS and associated PTCS. Furthermore, previous reports are being reviewed and the possible pathophysiology is discussed.
Discussion
The natural course of AS is associated with high morbidity and mortality if not being diagnosed timely and treated appropriately [
16]. AS is associated with a plethora of ophthalmological abnormalities, predominately posterior embryotoxon, optic disc drusen, angulated retinal vessels, and pigmentary retinopathy [
17]. In the majority of patients, normal vision can be secured [
18]. PE is the most common sign of elevated ICP in PCTS, which can lead to progressive visual loss, when left untreated [
26]. Although PE is not associated commonly with AS, concomitant congenital optic disc anomalies can be misinterpreted as PE and consequently result in misdiagnosis and unnecessary treatment [
5,
17].
The typical patient with primary PTCS or IIH is a young obese woman in childbearing age [
12,
29]. Establishing the diagnosis of primary PCTS in a typical patient is mostly a straightforward process based on the 2013 revision of the Friedman & Jacobson criteria [
12]. These require that in the presence of PE the opening pressure measured at lumbar puncture is elevated, the CSF composition is normal, there is no evidence of neurological deficits except for cranial nerve abnormalities, and there are no pathological findings in MRI with and without gadolinium [
5,
11,
12]. In contrast, the clinical profile of pediatric PCTS differs widely. Pediatric patients frequently remain asymptomatic but PE is incidentally diagnosed in up to 30% during a routine eye examination [
4,
13,
27,
28]. Correct diagnosis in pediatric patients is challenging. Opposite to adults, in children gender distribution is equal and weight is not a contributing factor for disease development. It has been estimated that up to 30% of children with PTCS and a normal body weight harbor a secondary etiology; therefore, appropriate identification of causative factors and conditions is essential prior further treatment [
3,
27].
The optimal treatment of PTCS in children remains debatable. The main stay of PTCS medical treatment in adults is acetazolamide. Surgical treatment (CSF shunting procedures, optic nerve sheath fenestration, and venous stenting) is indicated when visual loss is progressive and/or symptoms are intractable despite maximal medical management [
14,
23,
28].
Although continuous ICP-monitoring is not routinely performed for diagnosing PTCS, it has been shown that its application is a helpful adjunct especially in atypical cases and when surgical treatment is considered [
23,
30]. Especially in pediatric patients, it can provide an accurate measurement of ICP, which is commonly overestimated through a lumbar puncture [
6]. An increased baseline ICP, large ICP fluctuations, and the presence of ICP-oscillations (A- and B-waves) during recordings further can confirm the diagnosis [
23,
30].
The occurrence of PCTS in patients with AS is exceedingly rare with only few patients having been reported thus far (Table
1). Identifying true risk factors is important for establishing the diagnosis of PCTS and also for understanding the pathophysiology of the disorder [
7].
Table 1
Summary of patients with PTCS and Alagille syndrome
Emerick et al., 2005 | 3 yrs./M | symptomatic, PE | Raised/24 | Not transplanted | ns/ns | Acetazolamide and dexamethasone | Full recovery | ns |
Narula et al., 2006 | 6 yrs./NS | symptomatic, PE | Raised/ns | 4 yrs./tacrolimus and steroids | Normal/no | Acetazolamide and prednisolone, LPS after 15 mo | PE resolved, normal vision | ns |
25 mo/NS | asymptomatic PE | Raised/ns | 16 mo/tacrolimus (changed from cyclosporine due to early rejection) | Elevated before PTCS development, normal after PTCS development/ns | Furosemide | Normal CSF pressure and vision | ns |
20 mo/NS | Asymptomatic PE | Raised/ns | Not transplanted | Normal/no | Repeated LP (3×) | Normal development and vision | ns |
Ertekin et al., 2010 | 5 yrs./M | Symptomatic | Raised/29 | Not transplanted | Elevated/yes, less than recommended levels | Repeated LPs, acetazolamide | Symptom free | ns |
Mouzaki et al., 2010 | 25 mo/F | Asymptomatic PE | Raised/37 | Not transplanted | Elevated/no | Acetazolamide | Improvement of PE | 0.5 |
13 mo/M | Asymptomatic PE | Raised/35 | Not transplanted | Elevated/no | Acetazolamide | Improvement of PE | ns |
Polemikos et al., 2020 | 4 yrs./M | Asymptomatic PE | Raised/48 | 3 yrs./cyclosporine, steroids, mucophenolat mofetil | Normal/no | Acetazolamide, VPS after 6 weeks | Complete resolution of PE | 12 |
Both hypervitaminosis and hypovitaminosis A are risk factors for PCTS, and may be relevant in AS since most patients have a fat-soluble vitamin deficiency of variable degree which necessitates supplementation [
15]. Previous reports have considered elevated vitamin A levels as causative agent of PCTS in AS, two of them in the absence of vitamin A supplementation [
21] and one while on receiving vitamin A and D in less than recommended levels [
10].
From a pathophysiological point of view, it has been hypothesized that an increased production of CSF or an increased resistance to CSF outflow is the underlying mechanisms for PTCS, whereas most evidence supports the latter, possibly due to a field effect involving epithelial membranes [
20]. Sheldon et al. proposed a neuroendocrine pathomechanism for pediatric PTCS. They hypothesized that in PTCS hormonal and metabolic factors regulate CSF production and CSF absorption ultimately leading to elevated ICP [
24]. Furthermore, genetic or epigenetic factors appear to be relevant for developing PCTS, based on previously reported familial cases of PTCS [
23].
In 89% of cases, AS is caused by mutations/deletions in the Notch signaling pathway ligand gene, JAGGED1, or the gene for its receptor, NOTCH2 [
16]. The Notch signaling pathway has an important role in vascular development. Disruption of this pathway results in abnormal vascular development and signaling, which may also contribute to the development of IIH [
15,
22]. Mouzaki et al. speculated that abnormalities in the microvasculature of the choroid plexus in AS patients could lead to abnormal CSF production or absorption, which in turn would cause intracranial hypertension [
21].
The occurrence of PTCS in AS patients after liver transplantation has been previously described in 2 cases by Narula et al. [
22]. While these patients were on tacrolimus, our patient was receiving cyclosporine, which has been related to the development raised ICP after renal, bone marrow, and heart transplantation. Nevertheless, based on the occurrence of intracranial hypertension in AS patients without liver transplant, it appears unlikely that the immunosuppressive medication solely resulted in PCTS, although it could have been a contributing factor [
22].
Due to its rarity, knowledge about treatment of PTCS in AS remains very limited. This is reflected by the few previously reported cases as outlined in Table
1. While medical treatment with acetazolamide, furosemide, and steroids was effective, there is only very little information on long-term efficacy. We here show that ventriculoperitoneal shunting may provide long-term relief and prevent recurrent PE. Relapse of PE due to growth-related dislocation of the ventricular catheter reinforces the need of ophthalmological and radiological follow-up examinations.
PTCS in AS is likely to be underdiagnosed because ophthalmological examinations are not performed routinely after initial diagnostic workup and due to the fact that the majority of patients remain asymptomatic [
22].
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