Table 1.
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Monogenic disorders in short children born SGA with normal head circumference

Syndrome [OMIM]Genetic defectInheritanceIncidenceMean BW/BL SDSClinical featuresLaboratory dataTreatment
Monogenic disorders with normal head circumference and proportionate short stature
GH deficiencyGH1, GHRHR, BTKAR, AD X-linked1:5.000−0.9/−0.6Wide variation in height deficit↓GH peak during GH stimulation test, ↓IGF-I, ↓IGFBP-3, ↓ALSGH treatment
Laron syndrome [262500]GHRAR or rarely AD≈500 cases−0.6/−1.6Wide variation in height, midfacial hypoplasia↑GH, ↓IGF-I, ↓IGFBP-3, ↓ALS, variable GHBPIGF-I treatment moderately effective
ALS deficiency [615961]IGFALSAR≈65 cases−2.2Mild to moderate short stature↓IGF-I, ↓IGFBP-3, ↓ALSNo data
3-M syndrome [273750, 612921, 614205]CUL7, OBSL1, CCDC8AR≈200 cases−3.1Facial features, normal mental development, long and slender tubular bones, reduced AP diameter of vertebral bodies, delayed bone ageNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Silver-Russell variant [616489]IGF2AD, paternal8 cases−3.9/−4.6Dysmorphic features like SRS, fulfilling the Netchine-Harbison criteria for SRS, including relative macrocephaly↑/normal GH, normal IGF-I, ↑/normal IGFBP-3, ↓ IGF-IIGH treatment likely as effective as in other genetic variants of SRS
Floating Harbor syndrome [136140]SCRAPAD≈52 cases−2.5Proportionate short stature, delayed bone age and speech, triangular face, deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, thin lipsGH deficiency described in some patients. ↑/normal IGF-I (mainly during rhGH treatment. Nl IGFBP-3Insufficient data
Noonan syndrome [163950]PTPN11 and 12 other genesAD or rarely AR1:1.000-2.500−1.0Short stature, facial dysmorphism, wide spectrum of congenital heart defects, pectus deformity, cryptorchidism, coagulation defectNl GH, IGFBP-3 ↓/normal IGF-IGH treatment registered in US and EU
Monogenic disorders with normal head circumference and disproportionate short stature
SHOX-associated short stature [300582]SHOXAD2-17% of short stature−0.4 −1.1Short forearm and lower leg, bowing of forearm and tibia, dislocation of ulna at elbow, Madelung deformity, muscular hypertrophy, radiologic signs at wrist and forearmNl GH, IGF-I, IGFBP-3GH has similar efficacy as in Turner syndrome; registered in many countries
Achondroplasia [100800]Act FGFR3AD1:15.000-40.000−0.7/−1.0Rhizomelic limb shortening, frontal bossing, midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, trident handNl GH, IGF-I, IGFBP-3Effects of GH considered insufficient
Hypochondro-plasia [146000]Act FGFR31:15.000-40.000—Rhizomelic limb shortening, limitation of elbow extension, brachydactyly, relative macrocephaly, generalized laxity, specific radiologic featuresNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Short stature with nonspecific skeletal abnormalities [616255]NPR2AD1-2% of short SGA and ISS−0.8/−2.3↑ sitting height/height ratio, shortening of metacarpals, phenotypic or radiographic indicators of SHOX HI (but no Madelung deformity)Nl GH, IGF-I, IGFBP-3Insufficient data
Brachydactyly type A1 [1112500]IHHAD1.6% of short SGA and ISS−/−1.4↑ sitting height/height ratio, shortening of middle phalanx of 2nd and 5th fingers with cone-shaped epiphysesNl GH, IGF-I, IGFBP-3Preliminary data GH treatment positive
Short stature/early-onset osteoarthritis or osteochondritis [165800]ACANAD1%-2% of short SGA and ISS−0.7/−1.5Proportionate or disproportionate short stature, with or without advanced bone age, brachydactyly, early-onset osteoarthritisNl GH, IGF-I, IGFBP-3Insufficient data
Syndrome [OMIM]Genetic defectInheritanceIncidenceMean BW/BL SDSClinical featuresLaboratory dataTreatment
Monogenic disorders with normal head circumference and proportionate short stature
GH deficiencyGH1, GHRHR, BTKAR, AD X-linked1:5.000−0.9/−0.6Wide variation in height deficit↓GH peak during GH stimulation test, ↓IGF-I, ↓IGFBP-3, ↓ALSGH treatment
Laron syndrome [262500]GHRAR or rarely AD≈500 cases−0.6/−1.6Wide variation in height, midfacial hypoplasia↑GH, ↓IGF-I, ↓IGFBP-3, ↓ALS, variable GHBPIGF-I treatment moderately effective
ALS deficiency [615961]IGFALSAR≈65 cases−2.2Mild to moderate short stature↓IGF-I, ↓IGFBP-3, ↓ALSNo data
3-M syndrome [273750, 612921, 614205]CUL7, OBSL1, CCDC8AR≈200 cases−3.1Facial features, normal mental development, long and slender tubular bones, reduced AP diameter of vertebral bodies, delayed bone ageNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Silver-Russell variant [616489]IGF2AD, paternal8 cases−3.9/−4.6Dysmorphic features like SRS, fulfilling the Netchine-Harbison criteria for SRS, including relative macrocephaly↑/normal GH, normal IGF-I, ↑/normal IGFBP-3, ↓ IGF-IIGH treatment likely as effective as in other genetic variants of SRS
Floating Harbor syndrome [136140]SCRAPAD≈52 cases−2.5Proportionate short stature, delayed bone age and speech, triangular face, deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, thin lipsGH deficiency described in some patients. ↑/normal IGF-I (mainly during rhGH treatment. Nl IGFBP-3Insufficient data
Noonan syndrome [163950]PTPN11 and 12 other genesAD or rarely AR1:1.000-2.500−1.0Short stature, facial dysmorphism, wide spectrum of congenital heart defects, pectus deformity, cryptorchidism, coagulation defectNl GH, IGFBP-3 ↓/normal IGF-IGH treatment registered in US and EU
Monogenic disorders with normal head circumference and disproportionate short stature
SHOX-associated short stature [300582]SHOXAD2-17% of short stature−0.4 −1.1Short forearm and lower leg, bowing of forearm and tibia, dislocation of ulna at elbow, Madelung deformity, muscular hypertrophy, radiologic signs at wrist and forearmNl GH, IGF-I, IGFBP-3GH has similar efficacy as in Turner syndrome; registered in many countries
Achondroplasia [100800]Act FGFR3AD1:15.000-40.000−0.7/−1.0Rhizomelic limb shortening, frontal bossing, midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, trident handNl GH, IGF-I, IGFBP-3Effects of GH considered insufficient
Hypochondro-plasia [146000]Act FGFR31:15.000-40.000—Rhizomelic limb shortening, limitation of elbow extension, brachydactyly, relative macrocephaly, generalized laxity, specific radiologic featuresNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Short stature with nonspecific skeletal abnormalities [616255]NPR2AD1-2% of short SGA and ISS−0.8/−2.3↑ sitting height/height ratio, shortening of metacarpals, phenotypic or radiographic indicators of SHOX HI (but no Madelung deformity)Nl GH, IGF-I, IGFBP-3Insufficient data
Brachydactyly type A1 [1112500]IHHAD1.6% of short SGA and ISS−/−1.4↑ sitting height/height ratio, shortening of middle phalanx of 2nd and 5th fingers with cone-shaped epiphysesNl GH, IGF-I, IGFBP-3Preliminary data GH treatment positive
Short stature/early-onset osteoarthritis or osteochondritis [165800]ACANAD1%-2% of short SGA and ISS−0.7/−1.5Proportionate or disproportionate short stature, with or without advanced bone age, brachydactyly, early-onset osteoarthritisNl GH, IGF-I, IGFBP-3Insufficient data

Abbreviations: act, activating; AD, autosomal dominant; ALS, acid labile subunit; AR, autosomal recessive; BL, birth length; BW, birth weight; GH, growth hormone; IGF, insulin-like growth factor; IGFBP, IGF binding protein; ISS, idiopathic short stature; SDS, standard deviation score; SGA, small for gestational age; SRS, Silver-Russell syndrome.

Table 1.
Open in new tab

Monogenic disorders in short children born SGA with normal head circumference

Syndrome [OMIM]Genetic defectInheritanceIncidenceMean BW/BL SDSClinical featuresLaboratory dataTreatment
Monogenic disorders with normal head circumference and proportionate short stature
GH deficiencyGH1, GHRHR, BTKAR, AD X-linked1:5.000−0.9/−0.6Wide variation in height deficit↓GH peak during GH stimulation test, ↓IGF-I, ↓IGFBP-3, ↓ALSGH treatment
Laron syndrome [262500]GHRAR or rarely AD≈500 cases−0.6/−1.6Wide variation in height, midfacial hypoplasia↑GH, ↓IGF-I, ↓IGFBP-3, ↓ALS, variable GHBPIGF-I treatment moderately effective
ALS deficiency [615961]IGFALSAR≈65 cases−2.2Mild to moderate short stature↓IGF-I, ↓IGFBP-3, ↓ALSNo data
3-M syndrome [273750, 612921, 614205]CUL7, OBSL1, CCDC8AR≈200 cases−3.1Facial features, normal mental development, long and slender tubular bones, reduced AP diameter of vertebral bodies, delayed bone ageNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Silver-Russell variant [616489]IGF2AD, paternal8 cases−3.9/−4.6Dysmorphic features like SRS, fulfilling the Netchine-Harbison criteria for SRS, including relative macrocephaly↑/normal GH, normal IGF-I, ↑/normal IGFBP-3, ↓ IGF-IIGH treatment likely as effective as in other genetic variants of SRS
Floating Harbor syndrome [136140]SCRAPAD≈52 cases−2.5Proportionate short stature, delayed bone age and speech, triangular face, deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, thin lipsGH deficiency described in some patients. ↑/normal IGF-I (mainly during rhGH treatment. Nl IGFBP-3Insufficient data
Noonan syndrome [163950]PTPN11 and 12 other genesAD or rarely AR1:1.000-2.500−1.0Short stature, facial dysmorphism, wide spectrum of congenital heart defects, pectus deformity, cryptorchidism, coagulation defectNl GH, IGFBP-3 ↓/normal IGF-IGH treatment registered in US and EU
Monogenic disorders with normal head circumference and disproportionate short stature
SHOX-associated short stature [300582]SHOXAD2-17% of short stature−0.4 −1.1Short forearm and lower leg, bowing of forearm and tibia, dislocation of ulna at elbow, Madelung deformity, muscular hypertrophy, radiologic signs at wrist and forearmNl GH, IGF-I, IGFBP-3GH has similar efficacy as in Turner syndrome; registered in many countries
Achondroplasia [100800]Act FGFR3AD1:15.000-40.000−0.7/−1.0Rhizomelic limb shortening, frontal bossing, midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, trident handNl GH, IGF-I, IGFBP-3Effects of GH considered insufficient
Hypochondro-plasia [146000]Act FGFR31:15.000-40.000—Rhizomelic limb shortening, limitation of elbow extension, brachydactyly, relative macrocephaly, generalized laxity, specific radiologic featuresNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Short stature with nonspecific skeletal abnormalities [616255]NPR2AD1-2% of short SGA and ISS−0.8/−2.3↑ sitting height/height ratio, shortening of metacarpals, phenotypic or radiographic indicators of SHOX HI (but no Madelung deformity)Nl GH, IGF-I, IGFBP-3Insufficient data
Brachydactyly type A1 [1112500]IHHAD1.6% of short SGA and ISS−/−1.4↑ sitting height/height ratio, shortening of middle phalanx of 2nd and 5th fingers with cone-shaped epiphysesNl GH, IGF-I, IGFBP-3Preliminary data GH treatment positive
Short stature/early-onset osteoarthritis or osteochondritis [165800]ACANAD1%-2% of short SGA and ISS−0.7/−1.5Proportionate or disproportionate short stature, with or without advanced bone age, brachydactyly, early-onset osteoarthritisNl GH, IGF-I, IGFBP-3Insufficient data
Syndrome [OMIM]Genetic defectInheritanceIncidenceMean BW/BL SDSClinical featuresLaboratory dataTreatment
Monogenic disorders with normal head circumference and proportionate short stature
GH deficiencyGH1, GHRHR, BTKAR, AD X-linked1:5.000−0.9/−0.6Wide variation in height deficit↓GH peak during GH stimulation test, ↓IGF-I, ↓IGFBP-3, ↓ALSGH treatment
Laron syndrome [262500]GHRAR or rarely AD≈500 cases−0.6/−1.6Wide variation in height, midfacial hypoplasia↑GH, ↓IGF-I, ↓IGFBP-3, ↓ALS, variable GHBPIGF-I treatment moderately effective
ALS deficiency [615961]IGFALSAR≈65 cases−2.2Mild to moderate short stature↓IGF-I, ↓IGFBP-3, ↓ALSNo data
3-M syndrome [273750, 612921, 614205]CUL7, OBSL1, CCDC8AR≈200 cases−3.1Facial features, normal mental development, long and slender tubular bones, reduced AP diameter of vertebral bodies, delayed bone ageNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Silver-Russell variant [616489]IGF2AD, paternal8 cases−3.9/−4.6Dysmorphic features like SRS, fulfilling the Netchine-Harbison criteria for SRS, including relative macrocephaly↑/normal GH, normal IGF-I, ↑/normal IGFBP-3, ↓ IGF-IIGH treatment likely as effective as in other genetic variants of SRS
Floating Harbor syndrome [136140]SCRAPAD≈52 cases−2.5Proportionate short stature, delayed bone age and speech, triangular face, deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, thin lipsGH deficiency described in some patients. ↑/normal IGF-I (mainly during rhGH treatment. Nl IGFBP-3Insufficient data
Noonan syndrome [163950]PTPN11 and 12 other genesAD or rarely AR1:1.000-2.500−1.0Short stature, facial dysmorphism, wide spectrum of congenital heart defects, pectus deformity, cryptorchidism, coagulation defectNl GH, IGFBP-3 ↓/normal IGF-IGH treatment registered in US and EU
Monogenic disorders with normal head circumference and disproportionate short stature
SHOX-associated short stature [300582]SHOXAD2-17% of short stature−0.4 −1.1Short forearm and lower leg, bowing of forearm and tibia, dislocation of ulna at elbow, Madelung deformity, muscular hypertrophy, radiologic signs at wrist and forearmNl GH, IGF-I, IGFBP-3GH has similar efficacy as in Turner syndrome; registered in many countries
Achondroplasia [100800]Act FGFR3AD1:15.000-40.000−0.7/−1.0Rhizomelic limb shortening, frontal bossing, midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, trident handNl GH, IGF-I, IGFBP-3Effects of GH considered insufficient
Hypochondro-plasia [146000]Act FGFR31:15.000-40.000—Rhizomelic limb shortening, limitation of elbow extension, brachydactyly, relative macrocephaly, generalized laxity, specific radiologic featuresNl GH, IGF-I, IGFBP-3Effect of GH considered insufficient
Short stature with nonspecific skeletal abnormalities [616255]NPR2AD1-2% of short SGA and ISS−0.8/−2.3↑ sitting height/height ratio, shortening of metacarpals, phenotypic or radiographic indicators of SHOX HI (but no Madelung deformity)Nl GH, IGF-I, IGFBP-3Insufficient data
Brachydactyly type A1 [1112500]IHHAD1.6% of short SGA and ISS−/−1.4↑ sitting height/height ratio, shortening of middle phalanx of 2nd and 5th fingers with cone-shaped epiphysesNl GH, IGF-I, IGFBP-3Preliminary data GH treatment positive
Short stature/early-onset osteoarthritis or osteochondritis [165800]ACANAD1%-2% of short SGA and ISS−0.7/−1.5Proportionate or disproportionate short stature, with or without advanced bone age, brachydactyly, early-onset osteoarthritisNl GH, IGF-I, IGFBP-3Insufficient data

Abbreviations: act, activating; AD, autosomal dominant; ALS, acid labile subunit; AR, autosomal recessive; BL, birth length; BW, birth weight; GH, growth hormone; IGF, insulin-like growth factor; IGFBP, IGF binding protein; ISS, idiopathic short stature; SDS, standard deviation score; SGA, small for gestational age; SRS, Silver-Russell syndrome.

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