The Journal of Clinical Endocrinology & Metabolism, 2022, 00, 1–11

https://doi.org/10.1210/clinem/dgac637
Advance access publication 10 November 2022
Approach to the Patient

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Approach to the Patient With Short Stature: Genetic
Testing
Reena Perchard,1,2,3 Philip George Murray,1,2,3 and Peter Ellis Clayton1,2,3
1
Department of Developmental Biology and Medicine, University of Manchester, Manchester M13 9PL, UK
2
Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester M13 9WL, UK
3
Manchester Academic Health Science Centre, Manchester M13 9PL, UK
Correspondence: Philip George Murray, MBChB PhD, Paediatric Endocrinology, Royal Manchester Children’s Hospital, Oxford Road, Manchester M13 9WL,
UK. Email: [email protected]; or Peter Ellis Clayton, MBChB MD, Paediatric Endocrinology, Royal Manchester Children’s Hospital, Oxford Road,
Manchester M13 9WL, UK. Email: [email protected].

Abstract
The first step in the evaluation of the short child is to decide whether growth parameters in the context of the history are abnormal or a variant of
normal. If growth is considered abnormal, system and hormonal tests are likely to be required, followed by more directed testing, such as skeletal
survey and/or genetic screening with karyotype or microarray. In a small percentage of short children in whom a diagnosis has not been reached,
this will need to be followed by detailed genetic analysis; currently, exome sequencing using targeted panels relevant to the phenotype is the
commonly used test. Clinical scenarios are presented that illustrate how such genetic testing can be used to establish a molecular diagnosis,
and how that diagnosis contributes to the management of the short child. New genetic causes for short stature are being recognized on a
frequent basis, while the clinical spectrum for known genes is being extended. We recommend that an international repository for short
stature conditions is established for new findings to aid dissemination of knowledge, but also to help in the definition of the clinical spectrum
both for new and established conditions.
Key Words: short stature, genetic testing, molecular diagnosis
Abbreviations: ACAN, Aggrecan; FGFR3, Fibroblast growth factor receptor 3; GH, growth hormone; ES, exome sequencing; IGF, insulin-like growth factor;
IMAGe, intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities in males; IUGR, intrauterine
growth restriction; MRI, magnetic resonance imaging; NH-CSS, Netchine–Harbison Clinical Scoring System; NPR2, Natriuretic peptide receptor 2; NR,
normal range; r-h, recombinant human; POLE, DNA polymerase epsilon catalytic subunit; SDS, Standard deviation score; SGA, small for gestational age;
SHOX, Short stature Homeobox-containing; SNP, single nucleotide polymorphism; SRS, Silver–Russell syndrome; WHO, World Health Organization.

Background to 80% of children (1, 2) with the higher percentage from

the 1994 study.
Short stature is one of the commonest presentations to the pedi-
The next phase of evaluation requires a combination of the
atric endocrinologist. The approach to establishing a clinical
following tests, guided by history and examination: general
diagnosis in the short and/or slowly growing child starts with
tests for system disease; a screen for endocrine disorders or,
a detailed history, with particular focus on growth patterns
if suspicion is high, detailed hormone axis stimulation testing;
and pubertal development in the direct and wider family.
a skeletal survey for those with obvious or measurement iden-
Physical examination should focus on looking for evidence of
endocrine or system disease and signs of recognized tified skeletal disproportion; a karyotype or a microarray ana-
growth-related syndromes. Auxological measurements in the lysis looking for chromosomal abnormalities, with microarray
proband, parent, and sometimes siblings on standardized being an important first-line test for short children with devel-
equipment are essential. Pubertal assessment graded against opmental delay; and directed genetic testing for those with clear
standard criteria is required. The current growth data (standing signs of a monogenic disorder. This will lead to a specific diag-
height, sitting height, arm span, weight, body mass index) and nosis in 35% of children (2).
any preceding measurements should be plotted on country- This will leave 15% of children with short stature of un-
specific charts if available, or World Health Organization defined etiology (2) in whom further genetic investigations
(WHO) charts for children younger than 2 years and could reveal a diagnosis, recognizing that the chance of iden-
Centre for Disease Control charts for those aged 2-18 years. tifying a molecular diagnosis increases as the severity of the
A bone age, based on skeletal maturity in the nondominant short stature (<−3 SDS) increases (3). This includes those
hand and wrist, completes the physical assessment. These with “idiopathic short stature,” a commonly used term used
data will provide a diagnosis based on growth pattern (con- to describe those children with a height below −2 SDS without
stitutional delay in growth, familial short stature, short fol- findings of disease following a complete evaluation by a pedi-
lowing being born small for gestational age [SGA]) in 50% atric endocrinologist (4). Other groups of short children

Received: 3 August 2022. Editorial Decision: 25 October 2022. Corrected and Typeset: 18 November 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail:
[email protected]
2 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0

in whom a molecular diagnosis can be found include (1) those and intervention may be required. In certain conditions, there
short following being born small for gestational age (S-SGA), may be evidence to support the choice of growth promoting
(2) those in whom there is a suspicion of a genetic disorder, therapies (recombinant human GH [r-hGH], recombinant hu-
but signs of a specific disorder are not obvious, and (3) those man insulin-like growth factor I [r-hIGF-I] or therapies that

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with an endocrine disorder in which a molecular diagnosis can directly modulate bone growth) and knowledge about the
be reached (eg, familial growth hormone [GH] deficiency or long-term benefit of such therapies to height, metabolic
congenital hypopituitarism). It is within these groups that fur- health, and wellbeing. The finding of diagnoses, such as
ther genetic (DNA) analysis can be carried out using ap- Bloom syndrome, or a chromosome breakage syndrome, can
proaches such as next-generation sequencing of exomes (ES) support the decision not to use such therapies because of back-
or genomes. Analysis of ES can focus on “targeted panels,” ground risk for malignancy development. There are therefore
based on genes known to cause similar phenotypes (eg, pituit- compelling reasons for undertaking such detailed testing in
ary hormone deficiency, growth failure in early childhood, skel- these groups of short children.
etal dysplasia; these panels can be extensive and as an example Targeted panels can include genes known to cause short
for skeletal dysplasia the UK panel, available through the NHS stature and genes known to impact on hormonal and basic cel-
National Genomic Test Directory, includes 386 genes), or use lular growth pathways, including those genes within growth
all the exome sequence data to find novel targets. The availabil- plates influencing cartilage/bone development and metabolism
ity of DNA samples from parents and unaffected siblings is (5, 6). A whole exome approach increases the opportunity to
helpful in determining the clinical significance of DNA variants. find novel targets, but the level of analysis to achieve this and
The value of such intensive investigation requires consider- to confirm the significance of variants is considerable.
ation. Achieving a specific diagnosis is a part of the overall We present a range of cases that illustrate the clinical
management of the child. It provides certainty and often sig- scenarios in which detailed genetic testing is indicated and
nificant reassurance to families that there is a “real, recog- how it contributes to the child’s management. These include
nized” cause, and for some children it ends a “diagnostic (1) well-defined endocrine disorders requiring a molecular
odyssey” in which the child has been subjected to multiple diagnosis, (2) those with a high likelihood of a genetic dis-
opinions and investigations. The diagnosis may provide prog- order, (3) short stature with endocrine abnormalities in
nostic information on likely height that will be achieved, and the context of a complex multisystem disorder, (4) SGA
importantly may define risk for other features that may de- with persistent short stature and dysmorphism, and (5) idio-
velop over a lifetime (eg, osteoarthritis, vascular malforma- pathic short stature. A pedigree for each scenario is shown
tions, obesity, cardiometabolic disease), for which screening, in Fig. 1.

Figure 1. Pedigree for each of the families presented in this paper. (A) Consanguineous family with likely IGHD1A (Case 1). (B) Autosomal dominant
disorder causing hypopituitarism with variable penetrance (Case 2). (C) Family with autosomal recessive mitochondrial disorder resulting in SGA
children with postnatal growth impairment (Cases 3 and 4). (D) SGA with complex multisystem disorder (Case 5). (E) Silver–Russell syndrome caused
by a CDKN1C mutation (Case 6). Only individuals who inherited the mutation on the maternal allele are affected. (F) Familial short stature due to SHOX
duplications with autosomal dominant inheritance (Cases 7 and 8).
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 3

Clinical Scenarios be caused by mutations in the GHR, STAT5B, or IGF-I genes.

Both Laron syndrome (GHR mutations) (8) and STAT5B de-
Well-Defined Endocrine Disorders Requiring a
fects (9) present with a clinical picture similar to that of GH
Molecular Diagnosis
deficiency with postnatal growth failure with relatively pre-

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Case 1 served head size. GH binding protein measurement can be use-
A 14-year-old was referred from her primary care physician ful in identifying the etiology of GH resistance, but assays are
with short stature. She had recently moved to the UK. She not routinely available in most centers, with more accessible
was born at term following an uneventful pregnancy with a targeted genetic testing providing a specific diagnosis.
birth weight of 2.25 kg. There was a history of admission to These genetic disorders can therefore still be approached
the neonatal unit for respiratory distress but no history of through targeted sequencing of a single gene following defin-
hypoglycemia or jaundice. Concerns about growth were ition of the biochemistry or where gene panels are easier to ac-
raised from early life and r-hGH treatment was started at cess, the clinician may choose to ask the laboratory to examine
6 months of age. She was treated intermittently, and full a single gene initially. This approach saves time and reduces
details were not available. Her brother, now an adult, had the probability of identifying variants of unknown signifi-
been treated with r-hGH for GH deficiency, but only achieved cance. In this case, we are awaiting the result of sequencing
a height of 157 cm, −3.0 SDS. His adult phenotype was con- of the GH1 gene.
sistent with GH deficiency. An unaffected brother, now adult,
had a final height of 172 cm, −0.8 SDS. Case 2
At presentation in the UK at 14.3 years her height was 96 cm A boy was brought to the endocrine clinic at 2 months of age fol-
(−10.6 SDS) and weight 13.1 kg (−10.8 SDS). She was pre- lowing a complicated neonatal period. He was born by forceps
pubertal. There was mid-facial hypoplasia. Maternal height delivery at term with a birth weight of 3.9 kg. He had a cleft lip
was 152 cm and paternal height 168 cm. Parents were first and palate which had been identified antenatally on the 20-week
cousins. Initial baseline testing was remarkable for extremely fetal anomaly scan. At 6 hours of age, he was admitted to the
low levels of growth factors: IGFBP-3 was 0.59 mg/L (normal neonatal intensive care unit with hypoglycemia and hyponatre-
range [NR] 2.58-6.40) and IGF-I was 11 μg/L (NR 123-552). mia. Cortisol levels taken when the blood glucose was 27 mg/dL
There was no evidence of other pituitary hormone deficits, (2.1 mmol/L) were suboptimal at 1.1 μg/dL (30 nmol/L).
with thyroid stimulating hormone, free thyroxine and cortisol Thyroid function testing demonstrated a low free thyroxine level
concentrations all normal and gonadotrophins low, consistent of 0.6 μg/dL (7.2 pmol/L) (NRs 1.2-2.4 μg/dL (15-31pmol/L))
with her prepubertal status. Karyotype was 46XX. with a normal thyrotropin level of 3.4 mU/L. He had an undes-
A primed glucagon GH stimulation test identified severe cended left testis and micropenis with undetectable gonadotro-
GH deficiency with a peak GH concentration <0.1 μg/L while phins. Serum IGF-I concentration was undetectable, and the
the pituitary magnetic resonance imaging (MRI) demon- MRI scan of the pituitary identified the presence of an ectopic
strated anterior pituitary hypoplasia. Treatment with r-hGH posterior pituitary with absent pituitary stalk and severe anter-
at 30 μg/kg/day for 6 weeks did not result in any improvement ior pituitary hypoplasia.
in IGF-I levels (<10 μg/L) or IGFBP-3 level (<0.5 mg/L). The The diagnosis of congenital hypopituitarism with multiple
diagnosis was therefore isolated GH deficiency type 1A pituitary hormone deficiencies was clear but unlike the first
(IGHD1A), and treatment with r-hIGF-1 was started with a case, it is more challenging to diagnose the genetic etiology
moderate improvement in height SDS to −8.8 at 17 years of through the clinical and biochemical findings. A complex cas-
age. cade of spatiotemporal expressed transcription factors and
The differential diagnosis at presentation with severe short signaling molecules control development of the pituitary
stature and low IGF-I levels was between GH resistance and gland (10). While congenital hypopituitarism with multiple
severe isolated GH deficiency but the glucagon stimulation pituitary hormone deficits can be subclassified into (1) chil-
test was able to define the biochemical phenotype. This in dren without midline deficits, (2) those on the septo-optic dys-
turn provides a very strong pointer to target genetic investiga- plasia spectrum, (3) those with midline deficits, and (4) other
tion. Genetic forms of isolated GH deficiency are most com- syndromic congenital hypopituitarism, the number of genes
monly caused by mutations within GH1 or GHRHR genes. associated with each group is high and there is overlap in
Isolated GH deficiency type 1A (IGHD1A) is an autosomal re- the genes associated with each of these groups. In this scen-
cessive disorder caused by complete loss of GH protein due to ario, a wide panel-based approach should be applied. In 170
homozygous deletions or nonsense mutations in GH1 (7). The congenital hypopituitarism patients, Vishnopolska et al iden-
clinical presentation is that of severe GH deficiency with pa- tified a genetic etiology in 15% using a panel of 67 genes (11);
tients initially responding well to r-hGH therapy but this re- there is therefore a relatively low yield of positive molecular
sponse can falter due to the development of anti-GH diagnoses in the subgroups of congenital hypopituitarism.
antibodies. GH antibodies had not been measured in this However in our child, a heterozygous frameshift mutation
case: this would have been an important investigation, but in GLI2 was identified (c.922delT, p.[Ser308Glnfs]) giving a
the assay is not routinely available in many centers. diagnosis of Culler–Jones syndrome (12). Younger twin sib-
In this family as in other cases of monogenic disorders af- lings have now also been diagnosed with this mutation.
fecting the GH–IGF-I axis defining the clinical phenotype
and biochemistry can lead to the likely genetic etiology. The Those With a High Likelihood of a Genetic Disorder
phenotype of severe GH deficiency with a profound lack of re-
sponse to treatment with r-hGH strongly pointed toward a Cases 3 and 4
mutation in the GH1 gene. Other disorders with a similar clin- Two siblings of Irish ancestry were referred for evaluation
ical presentation include resistance to GH which presents with following a clinical diagnosis of 3-M syndrome. The older
high levels of GH and low levels of IGF-I and IGFBP-3 and can male sibling was born at term with a birthweight of 2.5 kg
4 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0

(−1.9 SDS) and a history of poor feeding in infancy. Short undervirilization, and an undefined immunodeficiency. He
stature prompted a pediatric endocrinology referral at 2.5 years also had microcephaly and significant learning difficulties. By
of age with height of −3.6 SDS and weight of −3.1 SDS. His age 7 years, growth stasis (with height velocity 1 cm/year) and
sister was born at term, following intrauterine growth restric- escalating weight velocity were evident, with central adiposity

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tion (IUGR) with a birthweight of 2.27 kg (−2.3 SDS). At 3 years and a protuberant abdomen. There was associated fatty liver
of age her height was −3.4 SDS and weight −3.1 SDS. Both and elevated triglycerides. By this time, he had developed mul-
siblings had a prominent forehead, a long thin philtrum, tiple vertebral fractures, warranting treatment with bisphosph-
deep set eyes and low set ears. Their facial features associated onate infusions. Abdominal protuberance continued into the
with short stature had initially raised the suspicion of 3-M teenage years, alongside wasting of gluteal and limb muscles.
syndrome (13). However, gene sequencing to look for muta- He went on to develop a hemophagocytic lymphohistiocytosis–
tions in CUL7, OBSL1 (exons 1-9) and CCDC8 (14) did type illness triggered by Epstein–Barr virus, and at 15 years
not reveal any mutation. Therefore, ES was undertaken, which of age, he received an unrelated donor stem cell transplant
revealed a homozygous pathogenic mutation in NDUFB3 which was successful. By age 19 years, he had ongoing adrenal
[c.64T>C, p.Trp22Arg] (13), indicating that these siblings insufficiency, severe short stature, hypertriglyceridemia, osteo-
had a mitochondrial disorder. Further investigations related penia, epilepsy, delayed puberty, and insulin resistance with
to this diagnosis demonstrated that the male sibling had a acanthosis nigricans. His older sister had died in early childhood
high signal in the globus pallidus on MRI scan and Wolff– of overwhelming sepsis infection related to immunodeficiency.
Parkinson–White syndrome on electrocardiogram. His sister The family were keen for a precise diagnosis to be made.
had a normal cranial MRI and electrocardiogram . During his early life, Sanger sequencing formed the main-
NDUFB3 encodes for a subunit of the mitochondrial mem- stay of genetic analysis and specific genes potentially respon-
brane respiratory chain NADH dehydrogenase (Complex I). sible for his phenotype were considered. In view of his
Although other patients have presented with features of mito- adrenal deficiency, the nuclear receptor DAX1 and NR5A1
chondrial disease such as lactic acidosis (13), these siblings were sequenced, and no mutations were found. These were
were well with no obvious metabolic dysfunction and normal unlikely targets in view of the complexity of his clinical fea-
lactate levels. Therefore, a diagnosis of mitochondrial disease tures. No mutations were identified in CDKN1C associated
would not have been suspected and would not have been diag- with IMAGe (intrauterine growth restriction, metaphyseal
nosed unless the ES had been undertaken. Making this diagno- dysplasia, adrenal hypoplasia congenita, and genitourinary
sis allowed the detection of Wolff–Parkinson–White syndrome abnormalities in males) syndrome.
in the male sibling. This is known to be overrepresented in pa- Reports of a syndrome associated with facial dysmorphism,
tients with mitochondrial disease (15). In some patients, the immunodeficiency, livedo and short stature (FILS syndrome)
first presentation of Wolff–Parkinson–White is with sudden (19), associated with a homozygous intronic variant
death, but if screened for (following a genetic diagnosis) and de- (c.4444+3A>G) in POLE (polymerase epsilon), had previous-
tected early, therapeutic ablation is possible (16). ly been described in a single large consanguineous family.
The sister had IUGR and was born SGA (13). This can be a POLE encodes the catalytic subunit of human DNA POLE1,
marker for a possible genetic cause for short stature, and if fetal which is an enzyme involved in nuclear DNA replication and
measurements are available, this may aid the clinician in deciding repair (20). Targeted genetic testing confirmed mutations in
which children should have genetic testing, even in the absence of POLE in our case and DNA testing for both unrelated parents
dysmorphic features. In addition, more than one sibling with the confirmed that they were carriers. An intronic variant
same clinical features increases the chances of finding a genetic (c.1686+32C>G) variant, which alters splicing, was identi-
condition. It is also important to note that in studies looking fied. This same variant was found in a total of 15 individuals
for genetic etiologies in short SGA children, being SGA may from 12 families (21). Our case also had a loss of function
not be a recognized feature of the monogenic disorder identified variant in trans (c.2091dupC, p.Phe699Valfs∗11), with these
(17). Thus, in some cases SGA may be an incidental finding. biallelic mutations leading to cellular deficiency in DNA poly-
These siblings demonstrate that there may be a degree of over- merase epsilon (21). As expected, his deceased sister, on
lap in the clinical features of very different conditions, and al- whom stored DNA was available, had the same mutations.
though clinical signs may point toward one diagnosis, an This case illustrates that perseverance with genetic investi-
absence of known mutations should lead the clinician to con- gations ended the diagnostic odyssey for this family, explain-
sider ES. As in this case, an important unexpected diagnosis ing not only the proband’s phenotype but the reason for his
was found, that has extended the phenotype of the mitochon- sister’s death. The associated increased malignancy risk in
drial disorder, previously recognized as a severe condition result- this condition resulted in referral to a specific clinic for surveil-
ing in death in early life (18), and provided another condition to lance, demonstrating an alteration in his management. This
add to the differential diagnosis of those with clinical features of case also contributed to POLE being established as the second
3-M syndrome. This syndrome is a good example of how genetic gene in which mutations cause IMAGe syndrome (21). This
testing has markedly increased the range of differential diagno- child presented more than 20 years ago. Today early use of
ses (Table 1) and will continue to do so. ES, indicated because of the complexity of the phenotype,
would have led to an immediate diagnosis.
Short Stature With Endocrine Abnormalities in the
Context of a Complex Multisystem Disorder SGA With Persistent Short Stature and
Case 5 Dysmorphism
A male infant had been under the care of pediatric endocrin- Case 6
ology from early life with significant prenatal and postnatal An 11-month-old girl was referred with growth impairment.
growth failure associated with adrenal insufficiency, severe Routine antenatal imaging was unremarkable at 12 and
Table 1. Differential diagnoses for 3M syndrome

3-M syndrome Floating IMAGe Isolated complex I Mulibrey nanism SHORT syndrome SOFT syndrome Silver–Russell syndrome
harbor syndrome deficiency
syndrome

Birthweight Mean −3.1 Mean −2.5 −2.0 to −4.0 −1.3 to −2.7 Mean −2.8 (range Mean −3.3 −2.7 to −4.3 Mean −2.7
SDS −4.0 to 0.5)
Adult height 115-150 M: 106 to 164 M: 160 (n = 1) Not reported 136-150 Mean 154 112 to 127 cm Mean 151
range (cm) F: 98 to 156 F: 142 (n = 1)
Cognitive Normal Variable Normal Normal Mild motor and Normal Normal social and Variable
function Delayed speech delay motor
speech development
Main Dolichocephaly, Delayed bone Metaphyseal Prominent forehead, Triangular face, S—short stature Triangular face, Macrocephaly,
features triangular face, age, dysplasia, long thin philtrum, short broad neck, H— hypotrichosis, triangular face,
prominent heels, expressive congenital may have raised misshapen hyperextensibility onychodysplasia, downturned mouth,
pectus deformity, language adrenal lactate, hypertrophic sternum, of joints/inguinal short long bones, limb asymmetry,
short thorax, winged delay, hypoplasia, cardiomyopathy, hepatomegaly, hernia hypogonadism, feeding difficulties,
scapulae, triangular male genital Wolf–Parkinson– increased tumor O—ocular depression high pitched voice fifth finger
hyperlordosis, hip face, anomalies White syndrome risk (Wilms, R—Rieger anomaly clinodactyly,
dysplasia, slender prominent ovarian stromal) T—teething delay brachydactyly,
long bones and nose, deep syndactyly,
vertebral bodies set eyes hypospadias,
cryptorchidism, café
au lait spots
Inheritance AR AD Paternally AR AR AD AR Most de novo
imprinted
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0

Genetics CUL7, OBSL1 (exons SRCAP CDKN1C c.64T>C, p.Trp22Arg TRIM37 mutations PIK3R1 mutations POC1A mutations 11p15 loss of
1-9), CCDC8 mutations mutations NDUFB3 mutation High prevalence methylation, maternal
mutations in Finnish UPD chromosome 7
population

3-M syndrome has a wide differential diagnosis. Syndromes with macrocephaly and normocephaly have been included. Differential diagnoses include isolated complex I deficiency, caused by a specific NDUFB3
mutation, as demonstrated by Cases 3 and 4.
Abbreviations: AR, autosomal recessive; AD, autosomal dominant.
5

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6 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0

20 weeks but following a low PAPP-A level in the mother, in- SDS) and weight of 21.1 kg (−3.0 SDS). He had been born by
dicating a greater IUGR risk, a further ultrasound at 30 weeks cesarean section at 37 weeks due to maternal pre-eclampsia
identified asymmetrical IUGR and oligohydramnios. Further with a birth weight of 2 kg (−2.3 SDS). Weight gain in infancy
imaging at 32 and 34 weeks demonstrated no further growth, was poor with a diagnosis of cow’s milk allergy and gastroeso-

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and she was delivered at 35 weeks. Birth weight was 1.43 kg phageal reflux. Through childhood, he had a persistent poor
(−2.76 SDS), length 39 cm (−3.08 SDS), and head circumfer- appetite and poor weight gain. He was noted to have hypermo-
ence 31 cm (−0.1 SDS). She was fed via nasogastric tube for bile joints, a trait also recognized in his mother. He had anxiety,
1 week and remained in the neonatal unit for 1 month due obsessive–compulsive traits, communication and social diffi-
to slow weight gain. culties and a poor sleep pattern. His younger brother had a
At 11 months of age, weight was 6.3 kg (−2.5 SDS) and length height of 111.4 cm (−2.1 SDS) at 7.2 years of age, and had joint
60.1 cm (−4.5 SDS) with body mass index of 16.6 (+0.4 SDS). hypermobility, constipation, and a poor sleep pattern.
Parental adjusted height SDS was −5.3. The mid face was noted Mother’s height was 150 cm (−2.1 SDS) and father’s 165 cm
to be small and the forehead protuberant. There was right sided (−1.7 SDS), with a distant paternal family history of short
hemihypertrophy with the left leg 1.5 cm shorter than the right. stature.
Development was normal. Baseline biochemical testing and Examination of the proband revealed no dysmorphic fea-
chromosomal microarray were normal. tures, no skeletal disproportion, nor any specific skeletal ab-
The clinical presentation is that of the child born SGA with normalities (eg, Madelung deformity). There was no
evidence of continued growth impairment during the first evidence of system or endocrine disease, confirmed on testing.
year of life. The presence of mid-facial hypoplasia with a protu- Microarray analysis revealed 2 rare copy number gains up-
berant forehead and hemihypertrophy raise a strong possibility stream of the Short stature Homeobox-containing gene
of Silver–Russell syndrome (SRS). Current consensus guidelines (SHOX) at Xp22.33 of 39 and 50 kb. One of these gains en-
recommend that the Netchine–Harbison Clinical Scoring compassed conserved noncoding regulatory element 2 with
System (NH-CSS) should be used to identify patients for genetic previous studies having associated such gains with short stat-
testing (22). She did not at that time meet the criterion to score ure (Fig. 2) (28-31). Despite this, the variant was classified by
on the NH-CSS for postnatal growth impairment as she was the laboratory as “of unknown clinical significance”. These
too young, nor did she meet the criterion for feeding difficulties. gains however were present in the younger brother and the
Despite this, the clinical impression was a diagnosis of SRS. mother, who both had heights <−2SDS. It is highly likely
Therefore, 11p15 methylation studies and testing for maternal that these gains have disrupted the function of the SHOX
uniparental disomy of chromosome 7 were undertaken and gene.
found to be normal. Rarer causes of SRS include gain of func- This family illustrate that (1) there may be no clearly defined
tion mutations in CDKN1C on the maternal allele (23) and loss pointers to a specific growth diagnosis, with familial idiopath-
of function mutations in IGF2 on the paternal allele (24). ES ic short stature accepted as an explanation, (2) other health is-
was undertaken in the proband, mother and father which re- sues can be present, some of which may be related to the
vealed a maternally inherited heterozygous missense variant eventual growth diagnosis (in this case communication and
in CDKN1C c.842G>C p.(Arg281Thr) (25). This missense social difficulties), and (3) first-line genetic testing with a
variant has not previously been identified in a child with SRS microarray analysis can reveal a diagnosis but in the absence
or IMAGe syndrome. It has not been detected in control data- of a recognized phenotype may be classified as a variant of un-
sets and is conserved across species. In silico analysis predicted known significance.
the mutation to be damaging using multiple programs. In keep- The American College of Medical Genetics uses a quantita-
ing with previous reports (23, 26), mother did not have any tive framework to assign copy number and sequence variants
clinical features of SRS and further family segregation studies into 1 of 5 categories (pathogenic, likely pathogenic, variant
identified she had inherited the missense variant from her un- of unknown significance, likely benign and benign) (32, 33).
affected father (the proband’s grandfather). To be classified as pathogenic the level of certainly is >99%,
Given the finding of this mutation and the association be- and for likely pathogenic >90%. The broadest level of cer-
tween CDKN1C mutations and IMAGe syndrome, a skeletal tainty of any category is that for the variant of uncertain sig-
survey was undertaken at 4.4 years of age which demon- nificance. With additional evidence, these variants can be
strated gracile long bones and a delayed bone age (3 years) later reclassified as pathogenic or benign. All sources of poten-
but no evidence of any skeletal dysplasia, while synacthen test- tial evidence including published literature, prediction of
ing confirmed normal cortisol secretion. pathogenicity and cases reported in public databases such as
Testing for methylation defects associated with SRS will re- ClinvarCNV should be explored. Importantly clinicians
main guided by the NH-CSS — testing is recommended for a should carefully assess how the phenotype of a disorder asso-
score of 4/6 or more, with consideration of testing for a score ciated with a variant of unknown significance matches the pa-
of 3/6. Uniparental disomy may be detected by a single nucleo- tient’s presentation in the context of affected family members.
tide polymorphism (SNP) array (but not a comparative gen- Providing such information to the laboratory may aid in vari-
omic hybridization array) and next-generation sequencing ant classification both for the index and future patients. In this
(27). For the rare variants like those in CDKN1C or IGF2, case, the laboratory reassigned these variants to be of likely
testing with targeted ES is required. pathogenic significance. We recognize in some cases there
will be a degree of uncertainty on the significance of a variant.
Idiopathic Short Stature Making a balanced judgement for the family may be helpful
for therapeutic decisions—in this case the decision to treat
Cases 7 and 8 both boys with r-hGH.
The proband presented to endocrinology for evaluation of Heterozygous mutations in SHOX cause Leri–Weill dys-
short stature at age 10 years with a height of 122.2 cm (−2.6 chondrosteosis and Madelung deformity, while homozygous
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 7

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Figure 2. (A) Schematic representation of the genomic SHOX region with upstream flanking region and location of conserved noncoding elements
(CNEs −2, −3, and −5). The distance from Xp/Yp telomere is indicated in kilobases, and areas where the patient’s copy number gains were found are
shown by the bars. One of the copy number gains encompasses CNE −2. (B) The same data presented using the Ensembl genome database for the
SHOX region showing the genomic location for the copy number gains (61). These are indicated by the large boxes. (Other gene browsers eg, UCSC can
be used).

Table 2. Diagnostic yield in copy number variant analysis studies of short stature patients

References n Selection criteria Diagnostic Short stature genes/microdeletion/duplication region

yield

Zahnleiter et al 200 Idiopathic short stature—sporadic in 92 and 10% PAX3, POMC, GCKR, 22q11, 3q29, 1q21, 2q33,
(54) familial in 108 1p36, and 1q21
Canton et al (55) 51 Born SGA with short stature present at ≥ 4 16% 22q11, 10q26, GAB1, IGFBP2, CSNK2A1, CHD8,
years. One of intellectual disability, GALNS, MIR421
developmental delay, or dysmorphic features
Wit et al (56) 49 Born SGA with short stature present at ≥ 3 years 16% mUPD7, mUPD14, SHOX, 15q26, 22q11, 2q31,
7p21, 8q24
Van Duyvenvoorde 162 Short stature of unknown origin both normal 12% SHOX, IGF1R, 15q26, 7q3, 1q44
et al (57) size and small at birth included
Hu et al (58) 119 Idiopathic short stature. SGA children 4% 22q11, 4q11, 4q12, Yp11
excluded.
Homma et al (59) 229 Short stature with dysmorphic features and 14% 1p36, 2p15, 2q31.1, Wolf–Hirschhorn syndrome,
developmental delay 12q14, Temple syndrome, 15q11, Smith–Magenis
syndrome, NF1 deletion syndrome, Miller–Dieker
syndrome, 22q11 deletion, SHOX
Hars-Isono et al 86 Short stature aged ≥ 2 years. Born SGA 9% 1q21, 22q11, Xp22.33, 19p13.12, 5q35, 10q36
(17)

mutations cause Langer mesomelic dysplasia (34). The ab- in these genes have been found in children with idiopathic short
sence of SHOX, located on the short arm of the X (and Y) stature, with the yield dependent on phenotype. For instance, in
chromosomes, is also a major contributor to short stature in short children with a degree of skeletal disproportion and/or a
Turner syndrome. SHOX was one of the first genes to be rec- minor skeletal abnormality, insufficient to make a diagnosis,
ognized as carrying pathogenic mutations in short children pathogenic variants in genes related to bone metabolism can
without a defined etiology (35). It is estimated that 3% to be found in ∼20% (36).
15% of children with idiopathic short stature carry a muta-
tion, that disrupts the expression and/or action of SHOX, in
Genetic Studies in Those With Short Stature of
the gene itself or its regulatory elements, which are located
both up- and down-stream. Undefined Etiology
Other genes associated with skeletal abnormalities include To date the most accessible whole genome assessment has
Fibroblast growth factor receptor 3 (FGFR3) (hypochondro- been that for copy number variation using either array com-
plasia and achondroplasia), Natriuretic peptide receptor 2 parative genomic hybridization or SNP arrays. The diagnostic
(NPR2) (acromesomelic dysplasia), and Aggrecan (ACAN) yield in published studies utilizing these technologies in
(spondyloepimetaphyseal dysplasia). Heterozygous mutations children with short stature of undefined etiology has been
8 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0

Table 3. Genes identified in exome screens in those with short stature of undefined etiology

References Targeted N Selection criteria Diagnostic yield Genes

or ES

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Fundamental Extracellular Paracrine Hormonal
cellular matrix signaling signaling
processes maintenance

Li et al (40) ES 330 Height < −2 SDS, plus 1 or 11% (those with PTPN11 PHEX FGFR3 GH1
Targeted 484 more of: height < −3SDS NF1 ACAN FGFR2 GLI2
height < −3 SDS alone) to 70% KMT2A COL2A1 FGFR1 IGF1R
Severe IGHD, MPHD, (those with ANKRD11 COL1A1 GALNS DUOX2
GHI, SGA no catch-up developmental SHOX RUNX2 NPR2
growth, additional delay) NIPBL
congenital anomalies/ SLCA12A1
dysmorphic features,
evidence of skeletal
dysplasia,
developmental delay,
microcephaly, mother
with recurrent
miscarriage
Fan et al ES 561 Height < −2 SDS 11% PTPN11 ACAN FGFR3 GH1
(39)a Age <18 years (24%a) BLM COL2A1 NPR2 GLI2
Excluded those with NF1 STAT5B
pituitary tumor, chronic IGF1R
disease, iatrogenic SS POU1F1
Perchard Targeted 263 Age ≥ 2 years 10% PTPN11 ACAN NPR2 GH1
et al (38) SS (height ≤ −2.5 SDS) HRAS RUNX2 GNAS IGF1R
without a defined TP63 MMP13 LHX4
etiology OBSL1
≥1 GH peak ≥7µg/L FANCB
GDF5
IKBKG
Hauer et al Targeted 200 Short stature with no 17% KRAS ACAN NPR2 GHSR
(60) ES identified cause MAP2K1 COL2A1 FGFR3 IGF1R
(common nongenetic PTPN11 PDE4D
causes excluded) NF1
KDM6A
TRIM37
Wang et al Targeted, 192 Height < −2 SDS, with no 2% PTPN11 IGF1R
(37) 1077 defined genetic etiology TRPV4
genes Could have comorbidities,
dysmorphic features or
other hormone
deficiencies

Example genes from these studies were included based on likelihood of pathogenicity and the frequency of variants in a gene.
Abbreviations: ES, exome sequencing; SS, short stature.
a
Fan et al (39): Genes identified in participants with isolated short stature have been included. Further variants were found in those with syndromic short
stature.

between 4% and 16% (see Table 2). Diagnostic yield is in- or apparently syndromic short stature (n = 304), causal variants
creased with increasing severity of short stature and where were found in 11% of the former group and 35% of the latter
children have additional features such as dysmorphism or in- group (39). Genes involved in fundamental cellular processes
tellectual disability. were prominent. In an even bigger study of 814 children with
In addition to copy number variant studies, both targeted short stature and at least one factor suggestive of a monogenic
and exome sequencing approaches have been used in children disorder, pathogenic/likely pathogenic variants, copy number
with short stature of undefined etiology with variable diagnos- variants or chromosomal abnormalities were found in 44%,
tic yield (Table 3). In a targeted gene approach using >1000 with RASopathy genes the most commonly identified (40).
genes, of which a third were associated with growth disorders, Overall, certain genes (Table 3) including PTPN11, ACAN,
in 192 short children without a diagnosis, only 2% had a NPR2, FGFR3, IGF1R, and GH1, appear to be the most fre-
pathogenic mutation that matched the phenotype (37). In an- quently identified in short children with undefined etiologies.
other targeted study using 232 genes in a cohort of 263 chil-
dren with idiopathic short stature (with 263 ethnically
matched controls), 10% had pathogenic or likely pathogenic Ancestry and Defining a Pathogenic Variant
mutations in known growth genes (38). Using ES in a larger Short stature may result from a single rare monogenic variant.
group of children with either isolated short stature (n = 257) Therefore, an essential consideration when determining
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 9

pathogenicity of a variant is its frequency within the relevant diagnostic process. It will be important that rigor in the attri-
ancestry (eg, African, European, South Asian). Online resour- bution of a diagnosis to a particular gene mutation is applied
ces such as the Genome Aggregation Database (gnomaD) (41) with due attention to the clinical context.
enable this, and the current dataset version (2.1.1) includes

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over 76 000 genomes from diverse ancestries.
Associations between SNPs and growth characteristics have Disclosures
been demonstrated. For instance in the European EPIGROW
R.P., P.M., and P.E.C. have nothing to disclose and have no
study (38), relationships between individual SNPs and short-
conflicts of interest in relation to this manuscript.
er sitting height and smaller head circumference as well as
lower IGF-I levels were found. Such relationships may also
vary with ancestry. A reanalysis was undertaken only in those
with Caucasian ancestry (42), with confirmation of the Data Availability
findings. Data sharing is not applicable to this article as no data sets
Despite this freely available online resource, and recog- were generated or analyzed during the current study.
nition of the value in studying diverse populations (43),
the majority of height genome wide association studies in-
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