Hemihypertrophy and limb asymmetry

Asymmetric body size: one side or one limb is larger (or smaller) than the contralateral side. Hemihypertrophy (true overgrowth of one side) and isolated lateralized overgrowth (formerly "isolated hemihypertrophy") sit at the benign-to-severe end of the asymmetric overgrowth spectrum. The mirror-image differential, asymmetric undergrowth (most prominently Russell-Silver), looks similar on first inspection and belongs on the list. The clinical importance: many of these conditions carry a real Wilms tumor risk and require ongoing abdominal surveillance.

The first task is to confirm asymmetry on standardized measurement (limb length radiographs, sequential photographs, segmental measurements). The second task is to decide whether the asymmetry is overgrowth or undergrowth. The third is to ask:

1. Is there a recognizable syndromic pattern? (Macroglossia, omphalocele, neonatal hypoglycemia → Beckwith-Wiedemann. Café-au-lait + plexiform neurofibroma overlying the limb → NF1.)
2. Is overgrowth localized (a single limb, a region) or generalized to one side?
3. Is it segmental and progressive? (Proteus is the prototype.)
4. Is the asymmetry actually undergrowth? (Russell-Silver pattern.)
5. Is there a vascular or lymphatic malformation? (Klippel-Trenaunay, CLOVES.)

Mosaicism is the unifying concept: most of these disorders are post-zygotic somatic mutations in growth-pathway genes (PI3K-AKT-mTOR, AKT1, PIK3CA), so the genetic test that wins is DNA from affected tissue (biopsy), not blood.

True hemihypertrophy with Wilms surveillance obligation

• Beckwith-Wiedemann syndrome (11p15.5 imprinting; loss of methylation at IC2, gain of methylation at IC1, paternal UPD11): the most common syndromic cause of hemihypertrophy. Look for macroglossia, omphalocele, macrosomia, neonatal hypoglycemia, anterior linear ear-lobe creases, posterior helical pits. Wilms tumor risk ~5-10% lifetime, highest with IC1 gain or pUPD subtypes. Abdominal ultrasound every 3 months until age 8 + serum alpha-fetoprotein every 3 months until age 4 (for hepatoblastoma).
• Isolated lateralized overgrowth (ILO), formerly "isolated hemihypertrophy": no other syndromic features. Still warrants Wilms surveillance because mosaic BWS-spectrum methylation defects can produce ILO with low yield on standard blood testing. Some centers send affected-tissue methylation.
• Simpson-Golabi-Behmel syndrome (GPC3, X-linked): macrosomia + coarse facies + organomegaly + supernumerary nipples + hemihypertrophy + Wilms risk.

Segmental / mosaic overgrowth (PI3K-AKT pathway)

• Proteus syndrome (mosaic AKT1 p.E17K): postnatal-onset, progressive, disproportionate overgrowth, cerebriform connective tissue nevi on plantar surfaces, lipomas, vascular malformations. The hallmark is progression: features expand over years.
• PIK3CA-related overgrowth spectrum (PROS): a continuum that includes CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/spinal anomalies), MCAP (megalencephaly-capillary malformation), hemimegalencephaly, and fibroadipose hyperplasia. Mosaic PIK3CA activating variants drive the spectrum.
• Klippel-Trenaunay syndrome: capillary-venous-lymphatic malformation + limb overgrowth + venous varicosities. Etiologically heterogeneous; many cases are PIK3CA-related (in the PROS spectrum).

Neurocutaneous and other localized overgrowth

• Neurofibromatosis type 1 (NF1): a plexiform neurofibroma in a limb can drive ipsilateral overgrowth and bony hypertrophy. Café-au-lait spots, freckling, and Lisch nodules give it away.
• Maffucci syndrome (mosaic IDH1/IDH2): multiple enchondromas + hemangiomas; limb-length discrepancy + risk of malignant transformation.
• Ollier disease (multiple enchondromatosis): asymmetric enchondromas without hemangiomas.

Asymmetric undergrowth (mirror-image differential)

• Russell-Silver syndrome (11p15 hypomethylation IC1, mUPD7): IUGR + relative macrocephaly + triangular face + clinodactyly + hemihypotrophy (one side smaller). This looks just like hemihypertrophy on the wrong side; the difference is the small side is the abnormal one, not the large side. The opposite imprinting defect of BWS at the same locus, with the opposite phenotype.

Acquired / non-syndromic

• Limb-length discrepancy after fracture, infection, or vascular event.
• Cerebral palsy with hemiplegia: the underused limb undergrows.
• Lymphatic or venous malformation with secondary overgrowth.

The diagnostic approach varies sharply between germline and mosaic conditions.

1. Confirm the asymmetry with standardized measurement (orthopedic limb length, sequential growth, photographs).
2. Document associated features: macroglossia, omphalocele/umbilical hernia, ear creases, hypoglycemia history (BWS); macrocephaly + capillary malformation (MCAP); cerebriform nevi (Proteus); café-au-lait (NF1); vascular malformation (PROS).
3. Methylation testing at 11p15 (BWS panel) on blood first, then affected-tissue biopsy if blood is negative and clinical suspicion remains. BWS mosaicism is missed in ~20-30% of blood-only testing.
4. Mosaic sequencing of affected tissue for suspected PI3K-pathway disorders (AKT1 for Proteus; PIK3CA for PROS/CLOVES/MCAP; IDH1/IDH2 for Maffucci). Skin biopsy from clinically affected tissue (e.g. lipoma, vascular malformation, overgrown limb skin) has higher mosaic allele fraction than blood; ultra-deep next-generation sequencing of affected tissue is the standard.
5. Abdominal ultrasound every 3 months until age 8 for BWS, ILO, and Simpson-Golabi-Behmel (Wilms surveillance protocol). Serum AFP every 3 months until age 4 for hepatoblastoma in BWS.
6. Brain MRI if neurologic features (megalencephaly, seizures, hemimegalencephaly).
7. Imaging of vascular and lymphatic anomalies (MR-angiography, ultrasound) as appropriate.
8. Chromosomal microarray if multiple anomalies suggest a contiguous-gene or aneuploidy etiology.