Case 2: A 20-month-old boy with asymmetric growth of the legs

A 20-month old boy with right-leg hyperplasia was referred to the authors’ institution for a genetic consultation. The child was born following an uncomplicated full-term pregnancy and delivery weighing 3150 g (20th percentile). There was no history of hypoglycemia in the newborn period. The parents first noticed a difference in the size of his legs when the child was one month of age. At four months of age, a leg circumference discrepancy was first documented (4 cm in the thigh and 2.5 cm in the lower leg). The child was referred to a vascular surgeon, who performed a Duplex ultrasound and documented normal arterial and venous blood flow, absence of arteriovenous malformations and varicosities, and possible lymphedema. At 12 months of age an orthopedic surgeon documented a leg length discrepancy of 2.5 cm.

At the time of referral, the boy was in good general health; his weight was 14 kg (99th percentile), height 85 cm (62nd percentile) and head circumference 47 cm (31st percentile). Discrete hyperplasia on the right side of the face was noted. Examination revealed significant discrepancies in all leg measurements – the right leg was 2.5 cm longer, with increased circumference at the thigh (4 cm), knee (3 cm) and lower leg (2.5 cm) (Figure 1). On focused inspection, there was no evidence of leg swelling, port-wine stains, vascular nevi, omphalocele, macroglossia, subcutaneous lipomata or ear creases/pits. He exhibited mild expressive language delay but otherwise normal development. Further diagnostic evaluation suggested the underlying diagnosis.

Figure 1).

Photographs (left and centre panels) and x-ray (right panel) of the patient at six months of age

CASE 2 DIAGNOSIS: ISOLATED HEMIHYPERPLASIA

The preliminary diagnosis made by the referring clinician was Klippel-Trenaunay-Weber syndrome (KTWS; Online Mendelian Inheritance in Man [OMIM] identification 149000). Isolated hemihyperplasia (IH; OMIM identification 235000) was considered as an alternative diagnosis because the diagnostic criteria for KTWS (vascular nevi, port-wine stains, arteriovenous malformations, varicosities at time of presentation) were not fulfilled. Features of other diagnoses that were considered, such as neurofi-bromatosis type I (cafe-au-lait macules) and Proteus syndrome (multiple lipomata), were absent (1). There were no phenotypic characteristics of Beckwith-Wiedemann syndrome (macroglossia, macrosomia or omphalocele). On assessment, the diagnostic considerations were atypical KTWS or IH. The distinction was considered to be extremely important because children with KTWS do not have increased risk for malignancies, while children with IH have a significantly increased risk for embryonal cancers. In a study involving 51 patients with IH, 16% had paternal uniparental disomy (UPD) of 11p15, 6% had hypomethylation at KCNQ10T1 (LIT1) and none had hypomethylation at H19 (2). There was evidence for somatic mosaicism in all eight cases of UPD. Four (50%) of the eight patients with UPD had tumours, whereas only six (15%) of the 40 patients without molecular alterations had tumours. Therefore, it appears that UPD at 11p15 significantly increases the risk for cancer in patients with IH. An analysis of the 11p15 region was undertaken in this patient, which may aid in the diagnosis and provide prognostic information regarding the risk of tumour development.

Cytogenetic analysis revealed a normal male karyotype (46 XY). The sequencing analysis did not show the E133K variant in the AGGF1 gene, reported to be present in some patients with KTWS. Analysis of the 11p15.5 region revealed hypermethylation at H19DMR (imprinting control region [ICR] 1) and decreased methylation at KvDMR (ICR2) compared with five normal controls and the proband’s parents (Figure 2A). To confirm UPD, the polymorphic markers D11S1984, D11S922, D11S1318 and D11S4088 in the Beckwith-Wiedemann syndrome critical region 11p15.5, and D11S1346 (11p15.3) outside the critical region, were assessed (Figure 2B and 2C). The results confirmed paternal UPD extending throughout the entire Beckwith-Wiedemann syndrome critical region, with a normal result for D11S1346.

Figure 2).

A Methylation-specific multiplex ligation-dependent probe amplification profile of H19DMR hypermethylation (indicated by ↑) and KvDMR hypomethylation (indicated by ↓), corresponding to paternal uniparental disomy at 11p15. B Fragment analysis – genetic profile of the marker D11S1984 (the paternal allele is indicated by the arrows). C Fragment analysis – genetic profile of the marker D11S4088 (the paternal allele is indicated by the arrows)

Based on the clinical findings and genetic testing, a diagnosis of IH was made. The risk of embryonal cancers was estimated to be high (lifetime risk of up to 50%) and regular tumour screening (daily abdominal palpation by parents, abdominal ultrasound four times per year and serial measurements of serum alpha-fetoprotein levels) was recommended. The present case illustrates the importance of careful clinical examination, diagnostic imaging, and genetic consultation and testing in children with limb hemihyperplasia.

CLINICAL PEARLS

• Any child with suspected IH should be referred to a clinical geneticist or a clinician with experience in overgrowth syndromes and vascular malformations.

• Until the diagnosis of IH is ruled out or once it is confirmed, the child should be regularly screened for abdominal tumours using abdominal ultrasounds and measurement of serum alpha-fetoprotein levels (3).