Deficiency of the short stature homeobox-containing (SHOX) gene is a frequent cause of short stature in children (2–15%). Here, we report 7 siblings with SHOX deficiency due to a point mutation in the SHOX gene. Index case was a 3-year-old male who presented for evaluation of short stature. His past medical history and birth history were unremarkable. Family history was notable for multiple individuals with short stature. Physical exam revealed short stature, with height standard deviation score (SDS) of −2.98, as well as arm span 3 cm less than his height. His laboratory workup was noncontributory for common etiologies of short stature. Due to significant familial short stature and shortened arm span, SHOX gene analysis was performed and revealed patient is heterozygous for a novel SHOX gene mutation at nucleotide position c.582. This mutation is predicted to cause termination of the SHOX protein at codon 194, effectively causing haploinsufficiency. Six out of nine other siblings were later found to also be heterozygous for the same mutation. Growth hormone was initiated in all seven siblings upon diagnosis and they have demonstrated improved height SDS.
Deficiency of the short stature homeobox-containing (SHOX) gene is a frequent cause of short stature in children [
The most common mutations involving the SHOX gene are deletions of various sizes which encompass either the SHOX gene itself or a regulatory enhancer region [
This Latino male is the third oldest child of a family originally from Mexico. He presented at the age of 3 years and 2 months for evaluation of short stature (Table
Results of growth hormone (GH) treatment in seven siblings with short stature due to SHOX haploinsufficiency.
Case | Sex | Age at onset of GH (years) | Bone age at onset of GH (years) | Duration of GH treatment (years) | Height SDS at initiation of GH | Height SDS in June 2014 | Change in Height SDS |
---|---|---|---|---|---|---|---|
1 | M | 3.8 | 3.5 | 9.3 | −3.1 | −1.06 | +2.04 |
2 | M | 2.9 | 1.5 | 8.5 | −2.71 | −0.77 | +1.94 |
3 | F | 9.3 | 8.8 | 4.5 | −2.48 | −1.42 | +1.06 |
4 | M | 10.6 | 10 | 4.3 | −2.42 | −1.83 | +0.59 |
5 | F | 1.8 | 2 | 4.3 | −2.57 | −2.23 | +0.34 |
6 | F | 1.5 | 1.3 | 3.5 | −3.00 | −2.52 | +0.48 |
7 | M | 1.8 | 2 | 2.1 | −2.26 | −1.41 | +0.85 |
He was born at full term, after an uncomplicated pregnancy and delivery, and his birth weight was near the 10th percentile. As an infant, his height initially was at the 10th percentile, then dropped below the 5th percentile at 22 months of life, and was far below the 3rd percentile by 33 months of life. He maintained his weight around the 10th percentile for the first 3 years of life. Family history is notable for maternal height of 143 cm (<3rd percentile) and paternal height of 156 cm (<3rd percentile), resulting in mid-parental target height of 156 cm. He also had five siblings with reported short stature and two siblings of normal stature.
On physical exam, his height was 85.4 cm (below 3rd percentile, height SDS −2.98), weight 11.8 kg (weight SDS −2.06). His arm span was 82.3 cm. He had no dysmorphic features. His testes were descended bilaterally, and he had a normal phallus.
Initial workup done for common etiologies for short stature revealed normal IGF-I, IGFBP-3, electrolytes, liver function tests, complete blood count, thyroid studies, sedimentation rate, and urinalysis. His bone age was congruent with his chronological age. No Madelung deformity was noted clinically or radiologically.
Because of his severe short stature, family history, and short arm span, a SHOX gene analysis was performed, which revealed a p.C194X sequence variant at nucleotide position c.582 in the SHOX gene, changing a nucleotide from C to A (c.582C>A) in codon 194. This creates a termination codon, which is predicted to cause truncation of the SHOX protein at codon 194. He was heterozygous for this nonsense mutation. The patient was started on growth hormone (GH) at 39
Height growth chart for Case
Six siblings of Case 1 subsequently presented for evaluation of short stature. The cases are listed in order of presentation to clinic, which occurred as they demonstrated decrease in growth velocity. Their clinical findings at presentation are summarized in Table
All siblings were noted to have height SDS less than −2.0 at the time of presentation. None of the siblings were dysmorphic. Cases 2 and 3 were the only siblings to have any additional abnormal phenotypes diagnosed radiologically: a shortening of the ulna in Case 2, with short 4th and 5th metacarpals, and Madelung deformity of the radial epiphysis in Case 3. Bone ages were either normal or slightly delayed, and workup for other etiologies of short stature was negative in all individuals, as with Case 1. Due to the confirmed family history for SHOX mutation, the SHOX gene analysis was performed in all individuals, and all 6 siblings were found to be heterozygous for the same, novel mutation. Growth hormone treated was initiated in all cases (starting dose 36–45
Height growth chart for Case
Case 3 was the eldest child, and her GH treatment was discontinued at age 13 years and 4 months as she neared completion of linear growth after menarche (Figure
Height growth chart for Case
This report describes a family with seven siblings with severe short stature at presentation. All are heterozygous for a point mutation of the short stature homeobox-containing (SHOX) gene that was included in SHOX database (
All cases had a mutation in exon 5, codon 194 (c.582C>A), that creates a termination codon. This results in a truncated protein and presumed haploinsufficiency. This truncated protein could potentially interfere with normal SHOX activity, but, at this time, the true mechanism is unknown. There are reports of mutations in the SHOX gene homeodomain affecting nuclear translocation [
SHOX deficiency, in addition to short stature, has a wildly varying phenotype, some features of which can act as a clue to the diagnosis. The Madelung deformity is a “spontaneous subluxation of the distal ulna forward” which results in the hand and forearm resembling a dinner fork [
The decision to obtain genetic testing in Case 1 was made based on the combination of his severe short stature and shortened arm span. His siblings were subsequently tested based on their known family history and significant short stature. When deciding when to pursue testing for SHOX deletion, there are a variety of clinical features to consider. Binder et al. [
Using the rationale that girls with Turner syndrome, whose short stature is believed to be due, at least in part, to SHOX haploinsufficiency, have had good response to GH treatment [
Consistent with previous observations, our patients all have a trend of improvement in their height SDS. In this family, there are a wide variety of ages at GH treatment onset as well as varied duration of GH treatment; however, we see that the two cases with the largest improvement in their SDS scores (Cases 1 and 2) also had the two longest durations of GH therapy. Based on the literature of girls with Turner syndrome, this is not surprising, as we would expect that the longer duration of treatment with GH would tend to lead to better improvement in height SDS [
Although there is known benefit of early initiation of GH therapy in older children, there is no precedent to direct the timing of GH initiation in a younger patient with known SHOX deficiency. Davenport et al. [
In this family, the parents were never tested for SHOX deficiency. Presumably, one of the parents is heterozygous for this novel mutation and likely the proband for this mutation. Assuming the second parent is unaffected, a 50% inheritance rate would be anticipated, though in this family the inheritance rate was higher, at 70%, creating a unique opportunity to study 7 siblings from the same family.
In summary, SHOX deficiency should be considered in the differential diagnosis of children with severe short stature even in the absence of typical phenotypic features. A short parent, as well as other siblings with short stature, may increase the possibility of SHOX deficiency. Unfortunately, the diagnosis can be done only by genetic testing, which is costly and may not be available in many countries, and, as a result, testing should be reserved for children for whom there is a moderately high clinical suspicion for SHOX deficiency. GH treatment improves height with more favorable outcome when it is used for longer duration prior to epiphyseal fusion.
Short stature homeobox-containing
Growth hormone.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
Elizabeth S. Sandberg acquired the clinical data, analyzed and interpreted the data, and drafted the manuscript. Lydia L. Snyder provided guidance to Elizabeth S. Sandberg in data acquisition, aided in analysis and interpretation of the data, and revised the manuscript. Karen J. Loechner diagnosed the index case, provided guidance in analysis and interpretation of the data, and revised the manuscript. Ali S. Calikoglu provided guidance to Elizabeth S. Sandberg in data acquisition, case report conception and design, analysis, and interpretation of data and revised the manuscript.