Earlier detection of hypochondroplasia: A large single‐center UK case series and systematic review

Hypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school‐age children, as limb‐to‐trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single‐center UK HCH‐cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.9%) and describe relevant case‐data for this subset of 13 patients. Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long‐bones or large head size on antenatal ultrasound scan. We then conducted a systematic literature review using PUBMED and MEDLINE, analyzing patients with HCH and related antenatal findings. Antenatally suspected (with subsequent molecular confirmation) HCH has been reported 15 times in the literature (2004–2019). Key markers (consistent in both groups) included reduced; femur length, humeral length and increased; biparietal diameter and head circumference. HCH is increasingly detected both antenatally and in infancy, contrary to previous descriptions. This is likely due to greater HCH awareness, improved imaging, and easier molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of younger patients with HCH is important with the advent of several targeted FGFR3 therapies currently in trials for Achondroplasia, that may soon be trialed in HCH.


Abstract
Hypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school-age children, as limb-to-trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single-center UK HCH-cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.9%) and describe relevant case-data for this subset of 13 patients. Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long-bones or large head size on antenatal ultrasound scan. We then conducted a systematic literature review using PUBMED and MEDLINE, analyzing patients with HCH and related antenatal findings. Antenatally suspected (with subsequent molecular confirmation) HCH has been reported 15 times in the literature (2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019). Key markers (consistent in both groups) included reduced; femur length, humeral length and increased; biparietal diameter and head circumference. HCH is increasingly detected both antenatally and in infancy, contrary to previous descriptions. This is likely due to greater HCH awareness, improved imaging, and easier molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of younger patients with HCH is important with the advent of several targeted FGFR3 therapies currently in trials for Achondroplasia, that may soon be trialed in HCH.

K E Y W O R D S
FGFR3, hypochondroplasia, prenatal diagnosis 1 | INTRODUCTION Hypochondroplasia (HCH), although a rare genetic disorder, is a relatively common skeletal dysplasia (SD) condition (some authors suggest the prevalence to be 1 in 33,000) caused by activating heterozygous mutations of the fibroblast growth factor receptor (FGFR3) gene (Bober, Bellus, Nikkel, & Tiller, 1999). The N450K variant accounts for around 70% of all reported patients (Rousseau et al., 1996). HCH is characterized by disproportionate short stature with limb rhizomelia, sometimes with facial dysmorphism (macrocephaly, frontal bossing, mid-facial hypoplasia) though often without and characteristic radiological features on skeletal survey (the commonest being; rhizomelic long bones with mild metaphyseal flare; lack of widening of the inferior lumbar interpedicular distances; mild-to-moderate brachydactyly; short, broad femoral necks; and squared, shortened ilia). (Bober et al., 1999) Diagnosis is based on clinical and radiographic grounds but is challenging due to often subtle features and phenotypic overlap with other SD conditions; thus, molecular confirmation is key. HCH has similar skeletal features to achondroplasia (ACH) but milder presentation with less severe medical complications.
Classically HCH presents in toddlers or school-age children (with decreased growth velocity leading to short stature) since limb-totrunk disproportion is often mild and easily overlooked during infancy (Stoll, Manini, Bloch, & Roth, 1985). The recent literature, however, demonstrates that HCH is clinically detectable earlier, even antenatally. Yet, this literature is often biased by patients with HCH with family history, priming clinicians to look for clinical features, rather than reflecting the earliest HCH detection in an unselected population. Thus, it does not reflect the unselected HCH presentation in the background population. Further bias includes patients reported without molecular confirmation of HCH, which considering the phenotypic overlap with other short stature conditions, creates doubt about the diagnostic accuracy or "purity" of the reports.
Documenting the earlier presentation (as compared with classical texts) of HCH in the unselected population is important, to prevent clinicians unduly discounting HCH diagnosis in infancy or antenatally.
We report experiences from a single UK center, HCH-cohort (n = 31) and systematically review the literature to explore antenatal detection of HCH.
In the systematic review, we identify all patients with antenatally detected HCH and highlight common detection themes. On analysis of the local cohort, we further identify patients with HCH that are both molecularly confirmed and clinically diagnosed antenatally and report the antenatal detection rate of HCH for the first time.

| BACKGROUND
HCH can be detected antenatally via sonography, based on short longbone findings with or without increased biparietal diameter (BPD) and subsequent molecular confirmation (Stoll et al., 1985).
Prenatal HCH diagnosis, based exclusively on fetal sonographic measurements, is difficult. In 1985, Stoll et al. proposed that it may be possible to diagnose HCH antenatally with the assistance of the presence of family history (Stoll et al., 1985). Five years later, Jones et al. reported the first patient with HCH that was diagnosed prenatally in the absence of family history. However, this was deemed difficult to replicate, attributing to the unremarkable family history and mild features when compared with other SD conditions (Jones, Robinson, & Sperrazza, 1990). Distinct HCH antenatal sonographic measurements were first reported in 1999 by Huggins et al., on a 25 weeks gestation fetus with HCH, born to a mother with ACH and a father with HCH (Huggins, Mernagh, Steele, Smith, & Nowaczyk, 1999). The longbones appeared shorter than expected, whilst the head measurements (BPD and head circumference [HC]) remained normal. The commonest skeletal dysplasia condition to consider antenatally when short long bones and macrocephaly are present is ACH. It is presumed short long-bones in the absence of increased head measurements could suggest HCH. Huggins et al. concluded that HCH may be distinguished based on sonographic measurements solely . More recently, Saito et al., reported two patients with HCH where the diagnosis of HCH could have been made based on previous antenatal sonographic measurements, despite the actual diagnosis being made at 3 years (Saito et al., 2016).

| Editorial policies and ethical considerations
Ethics committee review for the local cohort was obtained (approval number 08/H0810/14). The systematic review aspect of the article by its nature is not subject to ethics review. Patient privacy and confidentiality have been protected where nonidentifiable local cohort data has been used.

| Cohort
The HCH MDT service/clinic at Evelina Children's Hospital (ECH) has an active cohort of 31 patients with molecularly confirmed HCH (April 2020), 13 of whom met the inclusion criteria for this study (with confirmed FGFR3 mutations-12 N540K and one R200C-and antenatal findings consistent with HCH). Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long-bones or large head size on antenatal ultrasound scan (US). We chose to only include patients with a molecularly confirmed HCH diagnosis as a clinical diagnosis of HCH (without molecular confirmation) have historically been mislabeled.
Exclusion criteria were patients with an immediate family member suspected/diagnosed with ACH or HCH (so that any antenatal detection or suspicion of HCH was made without a priori knowledge, enabling determination of an "antenatal HCH detection rate" [AHDR] in its purest form without bias) and patients that were suspected with HCH but the pregnancy was terminated without molecular confirmation and absence of clinical postmortem findings (as such information is important to confirm that the diagnosis of HCH is secure).

| Systematic review
A systematic, retrospective search for reviews and primary research studies (short reports and case reports/series) was conducted using PubMed and MEDLINE databases, as shown in Figures 1 and 2 were "title and abstract" screened, and results were merged from PubMed and MEDLINE. A full-text screen was undertaken by three independent assessors and any discrepancies settled by group discussion.
The inclusion and exclusion criteria for patients with HCH in the systematic review were the same as in the ECH cohort. All 15 patients with HCH identified through the systematic review were clinically suspected as having HCH based on antenatal US findings and had molecular confirmation by age 3 years. Age three was used as a cutoff as before this is uncommon for patients to present with clinical HCH. Terminated pregnancies were only included when there was clinical documentation of molecular confirmation of HCH. Patients with intermediate ACH-HCH were excluded (to ensure an unambiguous cohort). Intermediate ACH-HCH cases are defined as; 1. those cases where the variant is not the classical variant for ACH (G380R) or HCH (N540K) and the variant itself has been reported in the literature with a phenotype of "severe HCH/mild ACH" by expert clinicians as with S348C (Bengur, Ekmekci, Karaarslan, Gunoz, & Alanay, 2020). In the case of S348C, the variant was reported three times with the same phenotype.
2. or those cases where the infant is compound heterozygote for N540K and G380R as one parent has ACH and one parent HCH, resulting in a blended phenotype and such patients were excluded (Huggins, Mernagh, et al., 1999).
There is no single clinical or radiological feature unique to HCH since there is much overlap with ACH; thus several parameters were used to make a clinical diagnosis (Bengur et al., 2020;Bober et al., 1999 Chen et al. (Bober et al., 1999;Pauli, & Legare, 1996). Ideally, FGFR3 sequencing should be performed if possible, as there are now many more mutations known to cause HCH than the well-known N540K hotspot (Jones et al., 1990).
The data discussed in our literature search pertains to US findings in the main, as opposed to radiological changes. The medical literature surrounding the radiological detection of HCH has emphasized the association of lack of interpedicular widening in the lumbar region with HCH (Panda, 2014;Sargar, Singh, & Kao, 2017). Diagnostic measures for HCH should include imaging of the anterior-posterior spine, which is of importance in identifying interpedicular distances, the decrease of which is more apparent with age (Bober et al., 1999;Panda, 2014). A lumbosacral spine radiograph taken of a 28-monthold child with HCH, referred for assessment of short stature and genu varum, was reported to show normal interpedicular distances (Ahn, Kim, Baek, Bae, & Lee, 2016). Further study, consisting of an 8-yearold boy and his 32-year-old mother showed unchanged interpedicular distances in L1-L5 regions for both patients (Chen et al., 2018). In the six patients from our cohort where molecular confirmation occurred postnatally, reasons for later detection included: antenatal measurements were mild and when born there was no clinical suspicion of SD conditions or testing was offered prenatally but was refused by parents.
Making an earlier diagnosis of HCH is important for many reasons, including the possibility of administering emerging therapies.
C-natriuretic peptide (CNP) analogues and drugs that modify the FGFR3 pathway are increasingly being trialed in younger patients, including under 6 months of age (BioMarin Pharmaceutical, 2020). It is expected that the same drugs being trialed in ACH will be efficacious in HCH. Some experts predict that earlier treatment will be more beneficial in terms of long-term growth and prevention of possible complications. Thus earlier detection of HCH is key. Additionally, detection in the antenatal period allows improved assessment and monitoring through the preambulant years, a period where current data is lacking.
Our study provides interesting data on the relative presentation of HCH as compared with ACH in a single UK center. HCH is a relatively common skeletal dysplasia, though accurate prevalence data is not readily available. Some authors suggest the prevalence to be 1 in 33,000 or close to that of ACH (1 in 20,000-25,000 live births) (Bober et al., 1999;Pauli & Legare, 1996) The earlier detection of known rare disorders (sometimes with a milder presentation) is becoming more apparent as imaging modalities improve, and our knowledge of rare disorders/genetic testing improves, so what we find in HCH is a paradigm for other rare disorders.
We believe the threshold for undertaking exome or genome sequencing upon the detection of fetal anomalies will lower. In the UK, the national fetal rapid exome sequencing service (R21) (launching late 2020) has five eligible categories for testing including "suspected skeletal dysplasia conditions," demonstrating increasing access to testing and lowering of the testing threshold (UK Genetic Testing Network, 2019). The R21 service is born out of research from the prenatal assessment of genomes and exomes (PAGE) study, which showed fetal exome yields of 8.5% in unselected cases of fetal anomalies, though further work and other studies showed that in selected cases (after genetics reviews) yields can increase to over 30% (Normand et al., 2018). Specifically the highest yield in any subcategory of fetal exome testing occurred in SD conditions (after case selection post genetics review) with rates of over 80% (Yang et al., 2020). Therefore, detection of SD conditions in the prenatal period will increase. We believe the identification of short FL in the presence of other markers suggestive of SD will lead to more genetic testing and likely increased pick up of SD conditions, that is, HCH and ACH at an earlier stage.
This will no doubt be useful for parents and clinicians since ACH in particular, can have very serious consequences in the infant period requiring monitoring and surveillance, for example, foramen magnum stenosis. With HCH, earlier detection, not only avoids protracted diagnostic investigations later in life but may also lead to an incidental diagnosis in any affected parents, so they can get the right help (as has been seen in our clinic). Again with the advent of several different FGFR3 targeted therapies, earlier detection will allow for earlier treatment which we hope will not only improve vertical growth but decrease potential complications.
In conclusion, this article supports the previous literature and strengthens it specifically by analyzing unselected patients with molecularly confirmed HCH. It reaffirms the increasing antenatal detection of HCH, along with the key sonographic parameters and highlights patients that were detected with HCH at an even earlier gestation (20 weeks) than previous. The increasing detection of HCH, both antenatally and in infancy is contrary to classical texts and is likely due to greater HCH awareness, improved imaging, and greater molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of earlier patients with HCH is important with the advent of several targeted FGFR3 therapies as such therapies may soon be trialed in HCH and are likely most efficacious during the earliest skeletal maturation.

ACKNOWLEDGMENT
We thank the patients and their family.