In this issue


Co-occurring mutations or modifying loci in the RAS-MAPK pathway may contribute to clinical variability among Noonan syndrome (NS) patients, suggest Ekvall et al (p. 1217).

They report on a young woman with cooccurring PTPN11 and SHOC2 mutations, symptoms typical of SHOC2-positive patients with NS, loose anagen hair (LAH), and several additional manifestations, some of which overlap with Costello syndrome.

Mutation analysis of the PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 genes revealed a co-occurrence of 2 previously identified heterozygous mutations in the index patient.One was SHOC2 c.4A >G; p.Ser2Gly, a de novo mutation, while PTPN11 c.1226G > C; p.Gly409Ala was inherited from her mother and also identified in her brother. Both mother and brother present with some NS manifestations, but neither had any NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype.

The researchers propose that the atypical phenotype of this patient with NS may be an additive effect in which the PTPN11 mutation acts as a modifier.


Findings by Akawi et al (p. 1236) call into question the identity of autosomal recessive Silver–Russel syndrome (SRS), a growth disorder, and suggest that all apparently recessive SRS families should be tested for mutations in CUL7and OBSL1.

Intrauterine growth retardation (IUGR) is a nonspecific finding occurring in about 0.17% live births. However, IUGR is also a significant feature of many recognized genetic syndromes involving growth disorders. These include SRS, three M syndrome (3-M), Dubowitz syndrome, and Mulibrey nanism.

Differentiation of 3-M syndrome from autosomal recessive SRS has been difficult because of SRS's phenotypic variability. Limb length asymmetry occurs in more than half of SRS cases, while characteristic radiologic findings of 3-M syndrome do not occur in SRS.

The researchers used SNP microarrays to investigate the cause of phenotypic features of SRS that show autosomal recessive inheritance in 3 consanguineous families, 2 from United Arab Emirates (UAE), and 1 from Jordan.

original image

Figure 1. X-ray of the lower limb of Patient 1 (III10) from family A showing normal bones.

The regions mapped by the researchers contained the genes CUL7 and OBSL1, which have recently been identified as the cause of 3- M syndrome. Subsequently, direct DNA sequencing of CUL7 and OBSL1 genes revealed novel mutations in both genes, including 2 mutations in OBSL1 and a nonsense mutation in CUL7. The researchers also found a sixnucleotide deletion in the UAE family, who had the typical features of 3-M.


A new system for classifying congenital limb deficiencies will help better determine the prevalence of specific phenotypes, write Gold et al (p. 1225).

The new system includes all potential phenotypes, lists a large number of distinct apparent causes, and illustrates the marked etiologic heterogeneity of limb deficiencies.

The researchers developed the system by identifying infants with limb deficiencies in the Active Malformations Surveillance Program at Boston's Brigham and Women's Hospital during 1972 to 1974 and 1979 to 2000. The researchers classified affected infants by the anatomy and apparent cause of their deficiencies.

The prevalence rate of all types of limb deficiency was 0.79 per 1,000. Upper limb deficiencies were significantly more common than lower limb deficiencies, but researchers found no significant difference in frequencies between deficiencies on the left and right sides of the body. Longitudinal defects were more common than terminal transverse defects. Intercalary defects were uncommon. Longitudinal defects were most likely to occur on the preaxial side of the limb. Almost half of affected infants had affected digits but normal long bones. The most common apparent cause of limb deficiencies was vascular disruption defects, with a prevalence of 0.22 per 1,000.

original image

Figure 3. Central hypoplasia of the fingers, with nubbins in the place of the second, third, and fourth digits at the level of the MCP joint. The thumb and fifth digit are not hypoplastic.