. Author manuscript; available in PMC: 2020 May 21.

Published in final edited form as: Curr Opin Pediatr. 2018 Aug;30(4):541–547. doi: 10.1097/MOP.0000000000000653

Table 1.

Monogenic causes that may present with isolated growth disorders

Gene	Function	Mechanism of isolated growth disorders (name of growth disorders)	Clinical phenotype
PAPPA2	cleaves IGFBP-3 and IGFBP-5 to increase IGF-I bioactivity	Loss-of-function mutations in PAPPA2 decrease biologically active IGF-1	AGA^α, small chins, mild microcephaly long fingers and toes, elevated IGF-I and IGFBP-3, bone age = chronological age, possibly low bone mineral density⁸
ACAN	proteoglycan extracellular matrix in growth plate	Not known	AGA/SGA^β, frontal bossing, midface hypoplasia, flat nasal bridge, anteverted ears, brachydactyly, bone age > chronological age^γ, with/without early-onset osteoarthritis, with/without osteochondritis dissecans, with/without intervertebral disc disease^10–15
SHOX	Not known	Not known (SHOX haploinsufficiency, Léri-Weill dyschondrosteosis)	AGA, disproportionate body proportion (decreased arm span and increased sitting to standing height ratio), short 4^th me metacarpal bones, Madelung deformities^17–18
PTPN11 and other rasopathy genes	Ras signaling regulator	Gain of function mutation increases ras signaling and suppress the production of IGF-1 (Noonan or Noonan-like syndrome)	AGA, down-slanted eyes, widely spaced eyes, low-set ears, low set posterior hairline, webbed neck, pulmonary stenosis, hypertrophic cardiomyopathy, scoliosis, undescended testes, coagulopathy, learning disability, renal anomalies, skin pigmentation lesions¹⁹
NPPC	C-natriuretic peptide; Regulator of ras signaling	Dysregulation of ras signaling	Hypertelorism, bone age = chronological age, small hands and feet, short 4^th metacarpal, mild facial hypoplasia²²
NPR2	Receptor for CNP	Dysregulation of ras signaling (Miura type-epiphyseal chondrodysplasia)	High-arched palate, mesomelic shortening of limbs, cubitus valgus, muscular hypertrophy, bone age < chronological age, short 4^th metacarpal bone, cone shaped epiphysis, short 5^th digit²³
FBN1	Formation of microfibril	Disruption of microfibril formation which alters TGF-β signaling (Weill-Marchesani syndrome 2, acromicric dysplasia, and geleophysic dysplasia)	AGA/SGA, round face, thickened skin, coarse facial features, bulbous nose, joint stiffness, brachydactyly, disproportionate short stature, various cardiac valve problems, aortic aneurysm, bone age < chronological age^24–25
IHH	PTHrP-IHH feedback loop	Dysregulation of chondrocyte hypertrophy (brachydactyly type A1)	AGA/SGA, short or rudimentary middle phalanges of some or all digits, disproportionate short stature^26–28
BMP2	A key regulator of chondrocyte proliferation and differentiation	Dysregulation of chondrocyte hypertrophy (brachydactyly type A2)	AGA, hypoplasia or aplasia of the middle phalanx of the index finger, other phalangeal abnormalities, midface hypoplasia, short nose, anteverted nares and long philtrum, with/without congenital heart disease^29–30

^α:

AGA, appropriate for gestational age

^β:

SGA, small for gestational age

^γ:

Advanced bone age is observed in most of patients with mutations in ACAN.