多位点印记障碍（MLID）是指除了导致主要临床表现的病变外，还伴有DNA甲基化改变的疾病。MLID在BWSp中的患病率高于其他印记性疾病，全基因组分析显示，大约三分之一患有IC2 LOM的BWSp患者存在MLID，但在节段性upd（11）pat或IC1 GOM患者中没有。在BWSp中，MLID几乎只涉及母系而非父系种系中的甲基化位点，尽管罕见病例显示IC2和IC1的LOM（后一个发现是生长限制性疾病Silver-Russell综合征（SRS）的特征）。 

罕见的BWSp MLID病例与NLRP2和NLRP5（编码NACHT、LRR和PYD结构域，包含蛋白质2（NLRP2）和NLRP5）中的双等位基因母体效应基因突变有关，因此这些基因中潜在的反式作用基因突变的可能性可能值得在遗传咨询中考虑。

可能是由于MLID中可变的甲基化改变和频繁的嵌合体，其对BWS临床表型的影响仍然不清楚，因此常规临床诊断试验不是这种共识的建议。

BWSp的复发风险取决于所确定的任何遗传或表观遗传缺陷的遗传病因和性质，以及其父母来源，因此建议家庭咨询应由在印记障碍领域有经验的个人进行，并应考虑到检测到的异常的精确性质（表5，R16，R17）。据报道，高达10–15%的BWSp病例是家族性的，最常见的原因是CDKN1C突变、染色体11p15异常和IC1内的基因改变。在这些病例中，遗传方式为常染色体显性遗传，但复发风险取决于传播受影响等位基因的父母的性别（表2）（表5，R17）。

致病性CDKN1C变异有50%的复发风险，如果突变是从母亲处遗传，则其临床表征可变。原则上，所有11p15 CNV和平衡易位与来源依赖表型的父母有50%的复发风险。在由于易位或倒位的不平衡分离而导致11p15父系重复的病例中，携带平衡重排的个体具有正常表型。在一些家系中，观察到BWS或SRS取决于11p15重复的父系或母系传播。父传一个重复的端粒结构域和母传一个缺失的着丝粒结构域也常导致BWSp的高复发风险。与端粒或着丝粒区域内较小CNV相关的表型和复发风险的预测可能很复杂，因为这取决于它们的大小以及涉及的基因和调控元件。

当发生在母体等位基因上时，内部IC1 CNV和SNV的复发风险高达50%，尽管在一些病例中观察到不完全外显率和可能的预期。BWSp MLID的罕见家族性病例可能由母体效应基因突变（例如，NLRP2或NLRP5突变）引起，并可能与非常高的复发风险相关。在存在其他分子缺陷的情况下，复发风险通常较低（表2）。

90%被诊断为典型BWS的儿童有巨舌症，BWSp是儿童期最常见的巨舌症病因。尽管在一些儿童中，巨舌可能会出现自发退化（由于生长速度下降和下颌骨生长增加的共同作用），但约40%的儿童接受了手术性舌复位。最常见的手术指征是进食问题；持续性流涎；发音困难；正畸问题，包括前突和前开口咬合的发展以及门牙间距/张开；以及由于不正常的美容外观和言语、进食和发音困难而导致的心理社会困难

The enlarged tongue is usually increased in size in all three dimensions and the aim of surgery is to reduce the tongue bulk while preserving normal shape and improving function. The most common surgical approach is anterior wedge resection but a variety of other techniques have been described125,128,129. Surgical complications, although infrequent, can include postoperative oedema of the tongue and wound dehiscence.

In rare cases, respiratory problems might require surgery to be performed in the neonatal period and preoperative tracheostomy might be required125. When obstructive sleep apnoea is suspected, an airway evaluation and appropriate further investigation with polysomnography can be used for objective assessment130,131 (TABLE 6, R33). In the absence of respiratory obstruction, surgery is generally delayed until at least age 12 months (when tongue size is more stable) (TABLE 6, R34–34). If the indication for surgery is unclear, the child’s progress should be monitored to determine if indications arise in the future. Long-term follow-up studies generally show favourable results of surgery in most cases with cosmetic improvement, reduced drooling, resolution of feeding difficulties, improved speech, adequate tongue mobility and, usually, no substantial effect on taste sensation126–128. Surgery has been reported to provide good outcomes in children who are operated on at a wide variety of ages, but mainly before 2–3 years125,127.

To facilitate objective assessments and accrual of accurate long-term prognostic data, surgery should, whenever possible, be restricted to a small number of units that can offer a multidisciplinary service (including an experienced surgical team) and long-term follow up (TABLE 6, R35–R38).

Exomphalos is a cardinal feature of BWSp (TABLE 1) and is preferentially associated with molecular defects occurring within the centromeric domain (IC2 LOM or CDKN1C mutations)10,13,16. To date, no specific recommendations have been given regarding the management of exomphalos occuring in patients with BWSp compared with isolated exomphalos in accordance with usual local practices (TABLE 6, R39).

Molecular investigations of apparently isolated exomphalos in neonates rarely detect a molecular abnormality in the absence of additional BWS features132.

Hypoglycaemia in BWSp is due to excess insulin and occurs in 30–60% of children with BWSp10,13,16. Although BWSp-related neonatal hypoglycaemia is often transient and resolves within a few days, in up to 20% of neonates it can persist beyond the first week of life and require medical treatments or even pancreatectomy in the most severe cases19.

Congenital hyperinsulinism is a rare condition with a range of causes19,133. In a cohort of 501 patients with hyperinsulinism (excluding patients with focal hyperinsulinism), ~6% had features of BWSp (most of whom had segmental upd(11)pat) and half of these patients underwent surgery due to persistent hypoglycaemia after optimal medication26.

Although low plasma glucose concentrations are common during the first 24 hours of life in all newborns, by day 3 plasma, plasma glucose concentrations in neonates are similar to those of older children, with a normal range of 3.5–5.5 mmol/l (60–100 mg/dL)134. A diagnosis of hyperinsulinism is based on evidence of increased insulin secretion and/or actions at the time of hypoglycaemia, including a detectable insulin level, suppressed levels of plasma β-hydroxybutyrate (ketones), suppressed levels of plasma free fatty acids and a glycaemic response to glucagon. Diagnosis should be made in consultation with an endocrinologist who is familiar with hyperinsulinism.

Neonates with suspected BWSp should be screened for hypoglycaemia (TABLE 6, R40 and R41) before discharge from the nursery. Neonates with confirmed hypoglycaemia should be treated to maintain a plasma glucose concentration >3.9 mmol/l (>70 mg/dL)134. Management of hyperinsulinism includes medical therapies such as diazoxide and somatostatin analogs (such as octreotide and lanreotide). Surgery (pancreatectomy) might be indicated if persistent hypoglycaemia occurs despite maximal medical therapies135. New therapies such as mechanistic target of rapamycin (mTOR) inhibitors (sirolimus) or glucagon-like peptide 1 receptor (GLP-1R) antagonists have been used in treatment of hyperinsulinism and very recently in BWSp136; however, to date, no specific management (medical or surgical) for hyperinsulinism has been evaluated in the context of BWSp (TABLE 6, R42).

Two genes that are implicated in congenital hyperinsulinism, ABCC8 and KCNJ11, map to chromosome 11p, and, although rare, some patients with BWSp might carry a heterozygous mutation in either gene26. If these genes are included in the isodisomy, then homozygosity for the mutation in disomic cells produces severe hypoglycaemia26. In cases of hypoglycaemia with hyperinsulinism and without other traits suggestive of BWSp, investigations for 11p15.5 methylation abnormalities might be considered.

Congenital heart disease is more prevalent in BWS than in the general paediatric population and cardiac defects occur in up to 13–20% of patients with BWS11,16,22 (TABLE 6, R44). Minor anatomical defects (for example, cardiomegaly, patent ductus arteriosus or patent foramen ovale and interatrial or interventricular defects) require echocardiographic monitoring until usual spontaneous resolution occurs (TABLE 6, R45). More severe defects might require surgical correction, although the management will be similar to that in sporadic cases of heart disease (TABLE 6, R47).

Congenital long QT syndrome has been reported in two families with BWS harbouring an intragenic deletion and a translocation at IC2 leading to inactivation of the KCNQ1 gene, which, although very rare, is associated with a risk of sudden death (TABLE 6, R46)85,102.

Cognitive development is usually normal in patients with BWSp; however, developmental delay can be associated with prematurity, severe hypoglycaemia, unbalanced chromosome rearrangements or paternal genome-wide UPD137 (TABLE 6, R48). The differential diagnosis should be carefully considered in patients with presumptive BWS and learning disability and without a 11p15 anomaly, as some overgrowth disorders (for example, Sotos syndrome, Malan syndrome and Simpson–Golabi–Behmel syndrome) are more frequently associated with developmental delay30,138–144 (Supplementary TABLE 2) (TABLE 6, R49).

Malformations of the central nervous system (for example, abnormal posterior fossae (including Dandy–Walker malformations) or abnormal corpus callosum or septum pellucidum) have been reported in rare patients with BWSp (chiefly with a defect involving IC2)83,145, and these features might need to be considered in children with neurological symptoms or signs (TABLE 6, R50).

The prevalence of nephro-urological anomalies in BWSp is 28–61%146. A variety of anomalies have been described; cortical and medullary cysts occur in ~10% of patients with BWSp and the prevalence of hypercalciuria and nephrolithiasis is increased compared to the general population 147. Although not all nephro-urological anomalies detected by ultrasonography will be of clinical significance, a minority of anomalies might be severe (and usually detectable prenatally), requiring medical or surgical management. Severe vesicoureteral reflux might cause kidney damage and recurrent urinary tract infections148 In addition, nephromegaly might be a marker of increased risk of Wilms tumour146.

Renal anomalies might occur in all molecular subtypes of BWSp, but only certain groups might be offered regular renal imaging for tumour surveillance. Management of the nephro-urological aspects of BWSp should be pragmatic and balance the benefits of presymptomatic diagnosis and treatment of critical obstructions and urinary tract infections for preserving renal function with the drawbacks of over-investigation for benign variants detected by surveillance. Thus, we recommend a nephrourological evaluation at clinical diagnosis and at the time of adult transition for any patient with BWSp, and screening for nephrocalcinosis and/or stones only in patients who undergo abdominal USS for tumour screening (TABLE 6, R51–55).

Embryonal tumours occur in ~8% of children with BWSp149. The most common types of embryonal tumour are Wilms tumour (52% of all tumours), hepatoblastoma (14% of all tumours), neuroblastoma (10% of all tumours), rhabdomyosarcoma (5% of all tumours) and adrenal carcinoma (3% of all tumours) 13. Although there are some differences in mean age at diagnosis between tumour types, the overall cancer risk is highest in the first two years of life and clinical experience suggests that the cancer risk then declines progressively before puberty, approaching the cancer risk of the general population. Currently, there is no evidence of an increased risk of malignant tumours in adulthood (Supplemental TABLE 3).

The tumour risk correlates with the BWSp molecular subgroup; patients with segmental upd(11)pat and IC1 GOM have a higher tumour risk than patients with CDKN1C mutations and IC2 LOM58. The four main molecular subgroups are characterised by a cancer risk gradient, with the highest risk in cases of IC1 GOM (28% risk), followed by segmental upd(11)pat (16% risk), CDKN1C mutation (6.9% risk) and IC2 LOM (2.6% risk) 13. In addition, there are also differences in the tumour types observed between molecular subgroups. Patients with IC1 GOM are mostly predisposed to developing Wilms tumour (observed in 24% of cases and accounting for 95% of malignancies in this group)13,14,149. Conversely, patients with IC2 LOM and CDKN1C mutations do not usually develop Wilms tumour, but rather develop other tumours such as hepatoblastoma, rhabdomyosarcoma and neuroblastoma. Thus, a study from 2016 reported a prevalence of Wilms tumour of ~0.2% (2/995) in patients BWSp and IC2 LOM149; Although, a report from 2017 suggested that the risk of Wilms tumour in patients with IC2 LOM might be underestimated, only a single patient with Wilms tumour and an IC2 epimutation was observed150 so that, when put together with previous reports of Wilms tumour in large cohorts of patients with BWSp, the overall prevalence of Wilms tumour with IC2 LOM is probably much less than 1%151. Patients with CDKN1C mutations are mostly predisposed to neuroblastoma13,14,149. Patients with segmental upd(11)pat are predisposed to develop any of the tumour types seen in BWSp (TABLE 3). Individuals with genome-wide paternal UPD seem to have a high risk of developing tumour types similar to those with segmental upd(11)pat, but with an increased incidence of hepatic and/or adrenal tumours extending into adolescence and young adulthood63,64,137,152.

Specific studies investigating the tumour risk in patients with isolated lateralized overgrowth and clinically diagnosed BWS with negative molecular testing are lacking. It seems plausible that the cancer risk in patients with isolated lateralized overgrowth who fall within the BWSp is linked to the type of 11p15.5 molecular anomaly. Indeed, the tumour risk in patients with isolated lateralized overgrowth and segmental upd(11)pat is estimated to be as high as 32–50%121,153.

Tumour screening in patients with inherited cancer predisposition syndromes aims to improve patient survival and reduce morbidity through earlier detection of tumours. However, no surveillance protocol can detect every tumour and there are both benefits and drawbacks to screening — the latter include the financial costs, morbidity that can result from investigating asymptomatic benign lesions detected on surveillance, and psychosocial burden of repeated investigations for the patient and family. There is no generally accepted risk threshold for instigating tumour screening strategies and it might vary according to regional medical and medicolegal practices and local healthcare systems. Although screening is considered for a tumour risk >1% in the USA, a risk of 5% might be considered an appropriate threshold in Europe9,154. Various protocols have been suggested for tumour surveillance in BWSp, usually comprising abdominal USS with or without measurement of αFP levels at various ages and intervals during infancy13,14,155. Traditionally, although most protocols have been applied to all cases of BWSp, the definition of specific epigenotype-tumour risk correlations provides a basis for more targeted surveillance protocols.