תסמונת בקווית-וידמן

הגדרה

Beckwith-Wiedemann syndrome (BWS) is a disorder of growth regulation exhibiting somatic overgrowth and a predisposition to embryonal tumours.¹Features include:

• Macroglossia

• Abdominal wall defects

• Visceromegaly

It was first described in 1964 by Dr H R Wiedemann, a geneticist from Kiel in Germany. Dr J Bruce Beckwith, a paediatric pathologist working in California, also described it in 1969. The severity of effect on the child is highly variable, with the majority minimally affected.

Pathogenesis

The underlying cause is unclear. 80% of cases have genotypic abnormalities on the distal portion of chromosome 11p. The reported pattern of inheritance is autosomal dominance with variable expression. There is contiguous gene duplication at band 11p.15.5.² This is always derived from the patient's father, whereas translocation and inversion are invariably derived from the mother. There appears to be aberrant genomic imprinting resulting from a defective or absent copy of the maternally derived gene - uniparental disomy.

Most sporadic cases lack apparent cytogenetic abnormalities. Only 2% carry inversions, translocations or deletions. 20% of sporadic cases have uniparental disomy.³ 50% have loss of methylation.

Most patients with BWS show biallelic expression of insulin-like growth factor 2 (IGF2) in various tissues - see under 'Presentation', below.

אפידמיולוגיה

Incidence

The incidence is estimated to be 1 in 13,700. Subfertility and assisted reproduction are associated with an increased frequency of BWS.¹

Recent work has suggested an association between genetic imprinting disorders (such as BWS and Angelman's syndrome) and children conceived with assisted reproduction techniques (ARTs) such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI).⁴⁵

הצגה

Increasingly commonly diagnosed at prenatal ultrasound.⁶ Suspicious features include:

• Increased abdominal circumference.

• Large kidneys.

• Large placenta, raised amniotic fluid volume.

• Protruding tongue.

• Large-for-gestational-age fetus.

• Raised alpha-fetoprotein with omphalocele.

תסמינים

• Hypoglycaemia.

• Poor feeding.

• Lethargy.

• Problems with breathing, eating and speech, relating to the severity of macroglossia.

סימנים

• Growth
  

  • Large for gestational age; the overgrowth in BWS is often the result of increased IGF2 action in the tissues. Birth weight and length are increased. Hemihypertrophy can be seen, where one part of the body, or usually all or part of one side of the body, is enlarged. This often becomes apparent in later childhood.

  • Accelerated growth (on 90th centile or above).

• Abdominal wall defects:
  

  • Omphalocele and umbilical hernia.⁷

  • Diastasis recti causing a 'pot-belly' appearance.

• Visceromegaly:
  

  • Enlarged liver, kidneys, pancreas and spleen are found.

• Facial abnormalities:
  

  • Large, prominent eyes.

  • Creases in earlobes and pit behind the upper ear.

  • Pinna abnormalities, low-set ears.

  • Raised fontanelle, prominent occiput.

  • Metopic ridge, prominent on forehead due to early closure of fontanelle.

• Others:
  

  • Seizures.

  • Cryptorchidism.

  • Early bone maturation.

  • Naevus flammeus - stork bite mark over eyelids and forehead.

  • Renal structural anomalies, nephrocalcinosis.

אבחנה מבדלת

• Fetal overgrowth syndromes - eg, Simpson-Golabi-Behmel syndrome, Perlman syndrome, Costello syndrome.

• Glycogen storage disorders - type 0 or 1.

• Hyperinsulinaemia.

• Hyperpituitarism.

• היפוגליקמיה.

• Nesidioblastosis.

• השמנת יתר.

חקירות

• X-ray long bones.

• Blood sugar testing.

• X-ray, ultrasound, CT/MRI scan of abdomen.

• Chromosome analysis.

מחלות נלוות

There is an increased risk of tumour development in children with BWS:

• The incidence of malignant tumours in reported cases is 5-10%.

• The most common of these is Wilms' nephroblastoma. This occurs in 5-7%. Others are hepatoblastoma and adrenal tumours. נוירובלסטומות are less common.

• The risk of cancer is age-dependent with most occurring by age 4 years. 95% have occurred by the age of 8 years.

ניהול

אמצעים כלליים

Screening for tumours:¹

• The child should have alpha-fetoprotein levels (marker for hepatoblastoma) monitored until 4 years old.

• Repeated abdominal ultrasound scans until 8 years old.

Hypoglycaemia:

• Screening for hypoglycaemia should be undertaken in the first few days of life.¹

• Hypoglycaemia should be rigorously avoided and treated, when necessary.

• Diazoxide can be used to inhibit insulin secretion.

Surgical

• If the tongue protrudes and interferes with speech and dental development, the child should be considered for reduction surgery before 4 years old.

• Abdominal wall defects will need early neonatal repair. Testes may need bringing down within the scrotum.

סיבוכים

Most can be anticipated and managed:

• Predisposition to embryonal malignancies:¹

  • Most of the tumours associated with BWS occur in the first 8-10 years of life.

  • The most common tumours are Wilms' tumour and hepatoblastoma. Other embryonal tumours include rhabdomyosarcoma, adrenocortical carcinoma and neuroblastoma.

  • The overall risk for tumour development in children with BWS has been estimated at 7.5% with a range of risk estimates between 4% and 21%.

  • Clinical indicators of higher risks of tumour development include hemihyperplasia, nephromegaly, and nephrogenic rests.

• Premature delivery.

• Monozygotic twinning (usually female and discordant).

• Neonatal hypoglycaemia; uncontrolled hypoglycaemia in infancy is thought to be the major aetiological factor in the reported low IQ in BWS, rather than congenital malformation.

תחזית

The prognosis is very variable but the severe end of the spectrum may involve intrauterine, neonatal or childhood death. Death may be due to complications arising from hypoglycaemia, prematurity, cardiomyopathy, macroglossia or tumours. In contract, mildly affected children often have only subtle problems, which do not affect their quality of life.¹