Non- syndromic children with short stature after SGA form a heterogeneous group, with a wide spectrum of clinical symptoms and responses to GH treatment. For many years, only very limited (epi) genetic causes were known, but the increasing use of next- generation sequencing, whole exome sequencing (WES), chromosomal micro arrays, RNA sequencing, and methylation arrays has resulted in the discovery of novel (epi)genetic causes of short stature after SGA birth. Some monogenic disorders are now being found in children previously considered to have idiopathic short stature (ISS). Most currently known monogenic primordial growth disorders present with short stature after an SGA birth as one of their clinical features. For clinical purposes, first the monogenic disorders with a normal head circumference and short stature (either proportionate or disproportionate) are presented (Table 1), followed by monogenic primordial disorders with microcephaly (Table 2) and finally the currently known imprinting disorders and methylation disturbances (Table 3). This division is arbitrary, because some genetic aberrations were first reported for children with a very characteristic phenotype (including microcephaly), while over time milder phenotypes have been recognized. The genetic disorders in short SGA children can also be presented according to a pathophysiological classification (see recent review).
Table1. Monogenic disorders in short children born SGA with normal head circumference
Table2. Monogenic disorders in short children born SGA with microcephaly
Table3. Imprinting disorders and methylation disturbances in short children born SGA
Monogenic Disorders with Normal Head circumference and Proportionate Short Stature
Children with GH deficiency due to a GH- 1 gene mutation or GH insensitivity as result of an inactivating mutation of GHR, or PIK3R1 or an activating STAT3 mutation, have a lower mean birth weight and birth length, but most of them do not fulfil the criteria for SGA. However, in the case of a very low serum IGF- I and low GH peak during a provocative test or in the case of lack of growth response during GH treatment in a short SGA child, one may consider testing for these genes, because short SGA does not exclude an abnormality in the GH- IGF pathway.
Heterozygous IGFALS mutations are found in short SGA children, but also reported in children with ISS. Serum IGF- I and IGFBP- 3 levels are low. GH treatment may increase growth in children with a heterozygous IGFALS mutation. Absence of acid- labile subunit (ALS) due to homozygous IGFALS mutations (OMIM 615961) results in low IGF- I and very low IGFBP- 3, birth weights varying from – 3.7 to – 0.1 SDS, while the effects of GH treatment are unknown.
3- M syndrome is characterized by pre- and postnatal growth failure and is caused by mutations in CUL7 (OMIM 273750), OBSL1 (MIM 610991) or CCDC8 (MIM 614205). It is associated with reduced IGF2 expression and increased H19 expression, as also found in Silver– Russell syndrome. Growth response to GH treatment is disappointing.
Recently, a paternal IGF2 gene mutation was reported which leads to features resembling Silver– Russell syndrome. GH treatment is likely to be as effective as in other genetic variants of SRS.
Floating– Harbor syndrome occurs due to heterozygous mutations in the SRCA gene ((OMIM 136140). Only 26% of such children are born SGA and the phenotype is often mild. Data on the effects of GH treatment are very limited.
Mulibrey nanism (MIM 253250) is caused by biallelic TRIM37 mutations. Most children are born SGA and remain short but the progressive cardiomyopathy and other clinical problems are much more important. There are no data on GH treatment.
Monogenic Disorders with Normal Head circumference and Disproportionate Short Stature
In most genetic disorders associated with disproportionate short stature, the genes are already abnormally expressed during fetal life which often results in a lower birth length SDS than birth weight SDS. The more severe forms of skeletal dysplasia can be easily diagnosed in young children, but clinical features can be so mild that many children are initially labelled as short SGA of unknown origin or ISS. Body disproportion and skeletal abnormalities can become more abnormal when the child becomes older. In each short SGA child, the clinician should therefore regularly assess body proportions, particularly in the case of a relatively lower birth length than birth weight. When an SGA child has disproportionate short stature (sitting/ height >2 SDS and/ or arm- span width > height), genetic testing can be an efficient diagnostic approach. A description of all skeletal dysplasias and their underlying genetic aberrations is be yond the scope of this chapter, but the most frequent ones in relation to SGA and short stature are given in Table 1.
Turner syndrome (TS), either due to 45XO or mosaicism, may ex plain disproportionate short stature after SGA. Birthweight is lower than normal, but only 30% are born SGA. It is nevertheless important to exclude TS in all short SGA girls when the height is a considerable distance below target height (>1.6 SDS, based on national growth references). The disturbed prenatal and postnatal growth is caused by short- stature- homeobox (SHOX) haploinsufficiency. A full description of the medical care for girls with TS is beyond the scope of this chapter, but GH treatment at higher doses than recommended for growth hormone deficiency (GHD) children improves growth and adult height. The younger age at GH start, the better the growth response and adult height will be.
Mutations or deletions in the SHOX gene can be present in short SGA children. These are located at the tip of the X and Y chromo some, and transmitted in a pseudoautosomal fashion. Bi- allelic inactivating SHOX mutations cause the severe Langer mesomelic dysplasia (OMIM 249700), while heterozygous mutations or deletions of SHOX or its enhancers (or even duplications) cause a milder skeletal dysplasia, Leri- Weill dyschondrosteosis with a Madelung deformity of the wrist (OMIM 127300) [37]. This mutation can pre sent as SGA or ISS, with minor or no dysmorphic features, and no or mild body disproportion (OMIM 300582), particularly SHOX enhancer deletions. Birth length and weight show wide variations (– 4.3 to 1.5 and – 3.3 to 3.2 SDS, resp.) [38]. GH treatment results in a similar growth response and adult height gain as seen in girls with TS syndrome.
Heterozygous activating mutations in FGFR3 lead to a wide range of disorders, including achondroplasia (OMIM 100800), hypochondroplasia (MIM 146000) and even proportionate short stature. Neonates with achondroplasia have a birth length around – 1 SDS, but SGA is uncommon. The effect of GH treatment on adult height results in a modest increase of +0.5 SDS [40]. GH is only registered for this condition in Japan.
Children with hypochondroplasia (OMIM 146000) have rhizomelic limb shortening, limitation of elbow extension, brachydactyly, and relative macrocephaly. It is a relatively frequent genetic mutation in children with SGA and ISS. GH treatment results in better growth in the first years, but there are limited data on adult height.
Heterozygous carriers of NPR2 mutations (OMIM 616255) show a similar phenotype to SHOX haploinsufficiency, with short fore arms and short lower legs (mesomelia), but without Madelung deformity. NPR2 mutations explain ~2% of cases with short stature due to SGA or ISS. No data on GH treatment are available.
Heterozygous mutations of Indian hedgehog (IHH) are associated with brachydactyly type A1 (OMIM 1112500), but may also have mild disproportion. Most children are born SGA for length, and 50% have shortening of the middle phalanx of the second and fifth fingers with cone- shaped epiphyses. No data on GH treatment are available.
A heterozygous mutation of ACAN (encoding aggrecan) leads to abnormal cartilage matrix formation, with mild skeletal dysplasia, spondyloepiphyseal dysplasia (OMIM 608361), or short stature without radiographic skeletal dysplasia (OMIM 165800). Approximately 30– 40% of cases are born SGA and 14% of short SGA children with a bone age advancement of 6 or more months, had a heterozygous ACAN mutation. However, bone age can be normal. Birth length SDS is always lower than birth weight SDS and patients often have early- onset osteoarthritis and/ or osteochondritis dissecans. At present, there are only limited data on the effects of GH treatment, either alone or combined with a gonadotropin- releasing hormone (GnRH) analogue and/ or an aromatase inhibitor.
Noonan syndrome may also explain disproportionate short stature after an SGA birth. Activation of the Ras/ Mitogen activated protein kinase (MAPK) signalling pathway results in a number of overlapping syndromes, so- called rasopathies, including Noonan (OMIM 163950), Leopard (OMIM 151100), Costello (OMIM 218040), Cardiofaciocutaneous (OMIM 115150) and Neurofibromatosis- Noonan syndromes (OMIM 601321). All have a varying degree of postnatal growth failure and sometimes there are no obvious clinical features. Twenty- four per cent (24%) are born SGA. GH treatment improves height SDS during childhood and can improve adult height. GH is registered for Noonan syndrome in the USA, but not in Europe and Japan.
Monogenic Disorders with Microcephaly and Short Stature
Children with a IGF1 mutation (OMIM- 608747) are born with a very low birth weight and length and microcephaly, although some have a milder phenotype. Recombinant IGF- I treatment is moderately effective. Children with complete loss- of- function mutations also have sensorineural deafness (OMIM- 608747).
Children with a heterozygous IGF1R mutation (MIM 270450) have a wide range of birth weight (– 3.5 to – 1.5 SDS), birth length (– 5.0 to 0.3 SDS) and head circumference (– 3.0 to 0 SDS [48]. The prevalence of heterozygous IGF1R mutations or deletions is estimated at 1– 2% in short SGA children. Other features include normal baseline serum IGF- I levels and very high IGF- I levels during GH treatment, early feeding problems, variable delay in psychomotor development, and mild dysmorphic features. GH treatment results in a moderate growth response. Homozygous mutations have a more severe phenotype.
Terminal 15q deletion with allelic loss of IGF1R leads to pre- and postnatal growth retardation and cardiac symptoms, intellectual disability, diaphragmatic hernia, hearing problems, aortic root dilatation, neonatal lymphedema, and aplasia cutis. Limited data on GH treatment are available.
Homozygous pregnancy- associated- plasma- protein- A2 (PAPPA2) mutations were recently found in short children with ISS or born SGA. They had progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density, and elevated levels of serum IGF- I, IGFBP- 3, IGFBP- 5, ALS, and IGF- 2. Lack of PAPP- A2 protein decreases the liberation of IGF- I from the ternary complex and likely results in lower IGF bioavailability. Two years of biosynthetic IGF- I treatment resulted in a height gain of +0.4 to 1.0 SDS.
Primordial dwarfism is a group of rare genetic disorders characterized by severe IUGR and SGA, extreme short stature, and distinct microcephaly, which occur as a result of disorganized molecular and genomic changes during embryonic development. Most children can be easily recognized, like those with Cornelia de Lange syn drome (OMIM 122470), Meier- Gorlin syndrome (OMIM 224690), microcephalic osteodysplastic primordial dwarfism (MOPD) types I (OMIM 210710) and II (OMIM 210720), and Seckel syndrome (OMIM 210600)]. There are no data on GH treatment, which is likely to be ineffective.
Smith- Lemli- Opitz syndrome (OMIM 270400) is an autosomal recessive disorder characterized by SGA, short stature, microcephaly, dysmorphic features, mild to severe mental retardation, and multiple malformations. Patients have decreased serum cholesterol levels due a deficient cholesterol synthesis as result of mutations of the 3beta- hydroxysterol- delta7 reductase gene (DHCR7). There are no data on GH, which is likely to be ineffective.
Disorders of DNA repair or genomic instability are frequently as sociated with SGA, short stature, and microcephaly. Bloom syndrome (OMIM 210900) is a DNA repair disorder caused by a mutation in the gene encoding DNA helicase RecQ protein- like- 3 (RECQL3) and features include skin hypersensitivity to sunlight, particularly recognizable on the face. Fanconi syndrome (OMIM 227650) has genomic instability and clinical features include an irregular pattern of skin pigmentations which increases over time, abnormalities in major organ systems, early- onset bone marrow failure, and a high predisposition to cancer. Other syndromes in this category are Nijmegen breakage syndrome (OMIM#251260), LIG4 (MIM 606593) and XRCC4 mutations (OMIM 616541), Cockayne syndrome (OMIM 216400) and Rothmund- Thomson syndrome (OMIM 268400). GH treatment is contraindicated in these conditions, given the unknown long- term effects on cell division and their predisposition to cancer,
