Table 6.
PROS Recommendations with lower AGREE II Tool scores
| A. Agreement score +++/++, Evidence score B: based only on consensus agreement and/or best practice (Methods and Figure 1) | |
|---|---|
| Section and PROS phenotype (see Table 1) | Recommendation |
| Genetic testing | |
| Klippel Trenaunay syndrome | The confirmation of a PIK3CA pathogenic variant in these patients can be quite challenging and obtaining affected tissue at the time of surgery may offer the best chance. If use of inhibitors is going to be considered, demonstrating the mutation will be necessary, so planning and coordination will be critical |
| Pre- and perinatal diagnosis | |
| PROS | In any pregnancy where the foetus is known to have PROS, pregnancies may be complicated by polyhydramnios, prematurity, and difficult delivery in case of megalencephaly (foetal MRI) and/or breech presentation. The foetal management team should be made aware of these complications and arrangements for delivery made accordingly |
| Critical care | |
| PROS | Request cardiology review in all individuals after diagnosis and follow-up as appropriate in case of a diagnosis of cardiac arrhythmia In the presence of vascular anomalies assess the risk of thrombosis, haemorrhage and infections |
| CNS overgrowth or dysplasia | |
| PROS | The decision to use endoscopic third ventriculostomy, a ventricular diversion procedure (ventriculoperitoneal, ventriculoatrial etc.) vs. suboccipital decompression is beyond the scope of these recommendations. However, a relevant surgical consideration is that these procedures can carry an elevated risk of blood loss and postoperative vascular complications (e.g., stroke). While the incidence of intracranial vascular abnormalities in PROS is unknown, these patients can be at risk for vascular dysregulation. Therefore, surgical management decisions require a well-versed multispecialty team lead by a neurosurgeon to make appropriate recommendations that are individualized on a case-by-case basis |
| MCAP with ventriculomegaly/hydrocephalus | Historically, many children with MCAP and ventriculomegaly were empirically shunted in the absence of evidence for clear hydrocephalus. Given the rapidly progressive nature of megalencephaly in MCAP (with the head OFC crossing centiles especially early in life) combined with the co-occurrence of ventriculomegaly, close monitoring of the child is recommended including (a) close monitoring of OFC progression and trajectory, (b) watching for any signs/symptoms of increasing intracranial pressure/hydrocephalus, (c) close inspection of the brain MRI scan by an experienced neuroradiologist for any signs of increased ICP and/or obstructive ventriculomegaly. The decision of whether to intervene neurosurgically (whether by shunting or a third ventriculostomy) should be ideally made by a multidisciplinary team |
| non-MCAP PROS with truncal involvement | This subset of patients are at risk for spinal lesions including spinal vascular malformations or lipomatous lesions. We recommend a referral to a neurologist for examination and the evaluation of spinal imaging |
| Epilepsy | |
| PROS | We recommend following standard guidelines for treatment such as those established by the International League Against Epilepsy (ILAE) and referral to an epileptologist or epilepsy centre, for additional considerations such as ketogenic diet or epilepsy surgery (Glauser et al., 2013; Wilmhurst et al., 2015 and Kwan et al., 2010) |
| PROS with drug resistant epilepsy | |
| PROS with drug resistant epilepsy and focal cortical dysplasia or unilateral cortical involvement | |
| Neurodevelopment | |
| non-MCAP PROS with disfiguring lesions | These individuals may particularly benefit from psychological support to develop coping strategies in case of lesions that impact their quality of everyday and relational life |
| Endocrinopathies | |
| PROS with hypoglycaemia | In several reported cases hypoglycaemia has gradually improved with age, with progressive increases in fasting tolerance allowing gradual diminution of nutritional support (Leiter et al, 2017), however variable patterns have been reported including later presentations (McDermott et al., 2018). This is unpredictable and means that intermittent re-evaluation of fasting tolerance may be warranted |
| PROS with hypoglycaemia and/or linear growth retardation | A trial of GH may be indicated. In this case careful follow up of linear growth and trajectory of overgrowth should be undertaken, in case pathological growth is exacerbated by GH. Pragmatic delay of GH therapy until after 2 years of age has been suggested, avoiding the major period of brain growth. There exists a theoretical possibility that GH may promote tumourigenesis in the context of PROS in the longer term, as an “oncogenic” PIK3CA variant is already present. Reassuringly, to date no excess risk of neoplasia has been discerned in untreated individuals with MCAP. There are limited reports only of GH therapy in individuals with molecularly proven MCAP to date. It has generally been well tolerated with a single exception, and in at least four cases it proved effective with no discernible adverse effects (Davis et al, 2020). Further evidence is required before a confident statement can be made about relative risks and benefits of GH therapy in GH-deficient PROS |
| Tumourigenesis | |
| PROS | Given the absence of systematic data, we recommend counseling the families on a case-by-case basis |
| Oral/Dental management | |
| PROS with asymmetric facial overgrowth | The most frequent problems are abnormal tooth eruption, dental crowding, gingival and periodontal pathologies and these should be treated as in the general population (see also Appendix) |
| Facial infiltrating lipomatosis | |
| Orofacial presentation by Koutlas et al 2021 | |
| MCAP | |
| B. Evidence score C: no evidence or consensus agreement/not currently specified as best practice (Methods and Figure 1) | |
| Approach to negative testing results | |
| PROS | Currently, there is no evidence to direct how many times re-testing or re-biopsy should be considered where the a priori clinical probability is high. Each case must be assessed individually, taking into account previous experience with each methodology, obtaining new samples, or the need for molecular confirmation in the case of targeted therapies (see also Appendix) |
| Somatic overgrowth (craniofacial, trunk-spine, limb) | |
| MCAP | There are no specific growth charts for MCAP yet, which makes monitoring weight gain challenging |
| Endocrinopathies | The options here are rational but currently untested, and should be undertaken only under endocrine guidance on an experimental basis with due informed consent |
| PROS with neonatal, insulin-dependent hypoglycaemia | Somatostatin/Diazoxide may be of benefit. In intractable cases dependent on intravenous glucose infusion use of an mTOR inhibitor such as sirolimus and/or a PIK3CA inhibitor may be considered |
| PROS with severe, intractable, hypoketotic, hyper insulinemic hypoglycaemia dependent upon IV glucose infusion | Consideration should be given to the exploratory use of an mTOR inhibitor such as sirolimus and/or a PIK3CA inhibitor |
| C. Important issues where there is not yet any consensus | |
| PROS | Surgical management of overgrowth tissue including orthopaedic |
| Surgical management of vascular anomalies and lymphatic malformations | |
| Management of haemorrhage; of inflammation and infections; of pain | |
| Management by interventional radiology | |
| Physiotherapy | |
| Testing of potential pharmacologic therapies | |