Table 2.
Endocrine, phenotypic, and genetic characteristics of patients diagnosed with 3M, Noonan, and Silver Russell Syndromes
| Pt no. | Diagnosis | Age at referral (years) | Sex | BW SDS | HSDS | BMI SDS | IGF–I SDS | Basal GH (µg/L) | Peak GH (µg/L) | Clinical Features | Genetic Variant | Diagnostic Modality | Predicted outcome (unpublished variants) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 3M syndrome | 1.1 | F | –3.8 | –4.9 | –0.4 | ND | 4.2 | 37.2 | Frontal bossing, hypermobile joints, protuberant abdomen. Elongated face Consanguineous parents |
Homozygous OBSL1 mutation (36) c.1359insA, p.Glu454Argfs*11 (CI093476)* |
CGS | — |
| 2 | 3M syndrome | 0.1 | F | –1.5 | –4.5 | 0.5 | –2.6 | 41.0 | 33.0 | Frontal bossing, depressed nasal bridge, hypermobility of joints, prominent heels, short fingers, trident hands, short rib cage, bilateral hip dysplasia. Consanguineous parents |
Homozygous OBSL1 mutation (36) c.1359insA, p.Glu454Argfs*11 (CI093476)* |
CGS | — |
| 3 | 3M syndrome | 3.0 | F | –5.2 | –5.7 | –4.7 | –3.3 | 9.1 | 15.0 | frontal bossing, depressed nasal bridge, bitemporal hair thinning with sparse hair, short neck, short trunk, joint hypermobility, prominent heels. Consanguineous parents |
OBSL1 Homozygous mutation (36) c.1359insA, p.Glu454Argfs*11 (CI093476)* |
CGS | — |
| 4 | 3M syndrome | 0.1 | F | –2.6 | –5.1 | 0.7 | –0.2 | 5.4 | 10.8 | Frontal bossing, prominent heels, hypermobile joints Consanguineous parents |
Homozygous OBSL1 mutation (36) c.1359insA, p.Glu454Argfs*11 (CI093476)* |
CGS | — |
| 5 | 3M syndrome | 1.0 | M | –1.6 | –6.4 | –2.3 | –2.5 | 2.1 | 18.2 | Prominent forehead, depressed nasal bridge, hypotonia, short neck, hypermobility, prominent heels, short chest Consanguineous parents |
Homozygous OBSL1 mutation (36) c.1463C>T p.Arg489* (rs121918216)* |
CGS | — |
| 6 | 3M syndrome | 4.6 | M | –3.2 | –7.4 | 1.5 | –2.5 | 6.0 | >32.0 | Frontal bossing, depressed nasal bridge, bitemporal hair thinning, high pitched voice Consanguineous parents |
Homozygous OBSL1 mutation (36)c.1463C>T, p.Arg489* (rs121918216)* |
CGS | — |
| 7 | 3M syndrome | 10.0 | F | –0.8 | –4.5 | 0.7 | ND | ND | ND | Frontal bossing, flat nasal bridge, relatively large head with increased antero-posterior diameter, mid facial hypoplasia, dolichocephaly, bushy eyebrows, mild hirsutism, lumber lordosis, and protuberant abdomen. Consanguinity ND |
Homozygous OBSL1 splice site mutation (37) c.2134+1G>A (CS148259)* |
Panel | — |
| 8 | 3M syndrome | 7 | M | ND | –2.0 | –0.1 | –2.6 | ND | 19 | Pectus carinatum and high- pitched voice Consanguinity ND |
Compound heterozygous CUL7 mutation c.3490C>T, p.Arg1164Trp (rs201135654)* and c.3349C>T, p.Arg1117Trp (rs375832364)* |
Panel | Both variants SIFT: Damaging, PolyPhen—2: Possibly damaging CADD score 23.1 for c.3490C>T and 28.1 for c.3349C>T |
| 9 | 3M syndrome | 0.3 | F | –5.8 | –5.5 | –0.6 | –1.1 | 22.5 | 26.7 | Frontal bossing, depressed nasal bridge, epicanthic folds, bilateral hip dysplasia Consanguineous parents |
Homozygous CUL7 mutation (38) c.2988G>A, p.Trp996X (CM121245)* |
WES | — |
| 10 | 3M syndrome | 1.6 | M | –3.7 | –7.4 | –2.6 | –2.4 | 5.1 | 9.9 | Triangular face, prominent sternum Nonconsanguineous parents |
Homozygous CCDC8 mutation (39), c.612dupG, p.Lys205fs*59 (rs752254407)* |
Panel | — |
| 11 | Noonan syndrome | 6.9 | M | 0.3 | –2.1 | –2.7 | –2.4 | 1.1 | >32 | Bilateral orchidopexy, right undescended testis, prominent eyes, low set ears, single palmer crease Consanguineous parents |
Heterozygous PTPN11 mutation (40) c.417G>C, p.Glu139Asp (rs397507520)* |
WES | — |
| 12 | Noonan syndrome | 8.9 | F | –2.1 | –3.2 | –1.6 | –2.4 | 21.7 | 10.5 | Low set ears, downward slanting eyes, hypertelorism, mild ptosis, low posterior hairline. Nonconsanguineous parents |
Heterozygous PTPN11 mutation (40) c.853T>C, p.Phe285Leu (rs397507531)* |
WES | — |
| 13 | Noonan syndrome | 13.1 | M | –3.0 | –3.8 | –1.5 | –2.6 | 0.4 | 26.6 | Nasal speech, frontal bossing but not typical Laron, Failure to thrive since birth, feeding difficulties, right undescended testes Nonconsanguineous parents |
Heterozygous SOS1 mutation (28) c.3418T>A, p.Leu1140Ile (rs375550588)* |
WES | — |
| 14 | Noonan syndrome | 9.4 | M | 1.2 | –2.0 | 0.1 | –1.2 | 1.0 | 10.3 | Low set ears, hypertelorism, joint hypermobility Nonconsanguineous parents |
Heterozygous SOS2 mutation c.572C>G, p.Pro191Arg (rs72681869)* |
Panel | SIFT: Damaging CADD score 23.4 |
| 15 | Silver Russell syndrome | 1.1 | M | –2.0 | –3.7 | ND | –2.8 | 12.6 | 38.7 | Midfacial hypoplasia, frontal bossing Nonconsanguineous parents |
11p15LOM | SRS testing | — |
| 16 | Silver Russell syndrome | 4 | F | –2.3 | –4.3 | –4.9 | –3.4 | 4.6 | 12.5 | Frontal bossing, blue sclera, high pitched voice, normal cranial circumference, small face Nonconsanguineous parents |
MatUPD7 | SRS testing | — |
Genetic variants in bold are not published. Patient variants in italics were previously reported in Storr et al. 2015 (26) and Shapiro et al 2017 (28).
Abbreviations: BW, birth weight; HSDS, height SDS; ND, not documented; WES, whole exome sequencing; CGS, candidate gene sequencing; SRS testing for loss of methylation on chromosome 11p15 (11p15LOM) and uniparental disomy for chromosome 7 (MatUPD7) was requested concomitantly by clinical geneticists in referring centers.
*Reference SNP ID number or “rs” ID, the identification tag assigned by NCBI to a group (or cluster) of single nucleotide polymorphisms (SNPs) that map to an identical location or reference as listed on The Human Gene Mutation Database.