Diagnostic guide to hypochondroplasia

Abstract.

Hypochondroplasia is a skeletal dysplasia characterized by disproportional short stature with rhizomelic limb shortening, caused by pathogenic variants of FGFR3, most frequently the p.Asn540Lys variant. However, affected individuals harbor a wide variety of pathogenic variants, accounting for the broad phenotypic spectrum of the disorder. Despite being closely related to achondroplasia, hypochondroplasia is a milder condition that was previously believed to be recognizable only in childhood, but not in infancy. However, the widespread use of prenatal ultrasonography and frequent diagnosis of fetal limb shortening have increased the number of hypochondroplastic neonates identified, thereby clarifying the early radiographic findings of the disorder. Radiological diagnosis of hypochondroplasia in children carrying the p.Asn540Lys variant is currently feasible in the neonatal period or even prenatally, using three-dimensional CT. Conversely, some individuals have a mild phenotype with minimal skeletal abnormalities, which hampers the differential diagnosis of hypochondroplasia and constitutional short stature. For a definitive diagnosis, genetic testing for FGFR3 is recommended. This diagnostic guide aims to assist in the early recognition of hypochondroplasia and to facilitate the management of affected children.

Highlights

● Hypochondroplasia is a skeletal dysplasia causing short stature, linked to FGFR3.

● p.Asn540Lys variant is common, although multiple other variants exist.

● Given the broad phenotypic spectrum, FGFR3 genetic testing is recommended.

Introduction

Hypochondroplasia (HCH) is a congenital skeletal dysplasia characterized by short-limbed short stature, particularly pronounced in the proximal segments of the limbs. Its mode of inheritance is autosomal dominant. The severity of HCH varies, ranging from individuals with radiographic findings similar to those of achondroplasia to those with mild abnormalities resembling constitutional short stature (1,2,3). Clinical diagnosis of HCH, based on clinical features and radiographic findings, can sometimes be challenging; therefore, a Japanese version of the “Diagnostic Guide to HCH” has been developed. This article was prepared based on the aforementioned Japanese version.

Etiology

With advances in molecular genetic testing, the causative gene for HCH is now recognized as FGFR3 (2,3,4). The 2023 revision of the international nosology and classification of genetic skeletal disorders identifies only FGFR3 as a gene associated with HCH (4). Approximately 70–80% of individuals with HCH have been reported to carry the FGFR3 p.Asn540Lys variant (c.1620C>A or c.1620C>G) (3); however, other FGFR3 variants at different loci have also been documented. These data are consistent with those of a previous molecular study on FGFR3 variant distribution in Japanese individuals with HCH (5). Conversely, there were reports of individuals in whom HCH was suspected based on clinical manifestations and radiological findings; however, no FGFR3 variant was identified (1, 6), which may be due to the technical limitations of genetic testing and phenotypic mimics of HCH.

Clinical Manifestations

Individuals with HCH present with limb shortening, which is particularly pronounced in the proximal segments, along with short stature; however, its severity is significantly milder than that observed in achondroplasia. At birth, apparent limb shortening is typically not observed, making clinical diagnosis in infancy challenging. Trident hands were generally absent. Mild developmental delays may be present (3). Over time, the physical characteristics become more pronounced, including short stature with a relatively long trunk, shortened limbs, a normal or slightly enlarged head, mild lumbar lordosis, a protuberant abdomen, and limited elbow extension and forearm supination. Genu varum is observed during childhood (2). Additional features described include a stocky build, small hands and feet with short fingers and broad digits, mild generalized joint laxity, lumbar lordosis with abdominal protrusion, learning difficulties, acanthosis nigricans, and temporal lobe epilepsy (3). Recently, practical strategies and pathways that aim to improve the recognition of key clinical and radiologic features associated with hypochondroplasia were proposed (7). The proposed prenatal key sonographic findings include short femurs (< 10th centile) with either an appropriate head circumference or macrocephaly (> 90th centile) for gestational age, leading to early suspicion and diagnosis of HCH. Reported adult heights range from 138 to 165 cm in males and 128 to 151 cm in females (3). In individuals with a confirmed p.Asn540Lys variant in the FGFR3 gene, the reported adult height was 143.6 cm (range: 131–154.5) in males and 130.8 cm (range: 124–138) in females (8).

Plain Radiographic Findings

The characteristic skeletal changes are similar to those observed in achondroplasia, albeit milder. Table 1 presents the diagnostic criteria (1) for HCH, as outlined in the HCH section of the Information Center for Specific Pediatric Chronic Diseases.

Table 1. Diagnosis of hypochondroplasia.

Below, the “Guide to Radiographic Diagnosis of HCH” provides a detailed description of the skeletal findings and illustrates representative individuals with HCH. Skeletal findings evolve throughout growth, making it crucial to be aware of age-related changes. Typical older children, as well as severe ones, are presented, highlighting the similarities in patterns and the gradient of severity. Children with severe HCH exhibit a closer resemblance to achondroplasia. A comparison of findings within the same child with HCH during the neonatal period and early childhood revealed that skeletal abnormalities are more readily identifiable in early childhood. Additionally, fetuses have been discussed in relation to achondroplasia.

Radiological assessment is based on standard frontal and lateral radiographs of the skull and spine, and frontal radiographs of the pelvis and extremities. To evaluate the pelvic bones, for example, assessment should be based on an anteroposterior view obtained in a recumbent position with hip extension, rather than a frog-leg lateral view or upright view. However, we should keep in mind that accurate positioning is not easy in young children, and inaccurate radiography is fraught with diagnostic errors.

Guide to radiographic diagnosis of HCH

Skeletal findings in older children

The proposal to establish HCH as a distinct disease entity originates from early descriptions by Ravenna (1913) and Leri and Linossier (1924), followed by subsequent discussions of Leri’s report by Maroteaux and Lamy (1964), as well as additional reports from various groups, including Kozlowski (1964). Descriptions of skeletal changes in older children were consolidated by Beals (1969), Kozlowski (1973), and Hall and Spranger (1979) (9, 10). The diagnostic findings are summarized as follows: the overall pattern of skeletal changes is similar to that observed in achondroplasia, although it is significantly milder.

Spine:

● Loss of the normal progressive increase in interpedicular distance in the caudal lumbar spine on frontal views

● Shortening of the pedicles on lateral views

● Posterior scalloping of the vertebral bodies

● Low position of the sacrum relative to the ilia*

*These findings are strongly influenced by projection and can be difficult to assess objectively.

Pelvis:

● Squaring of the iliac bones, with loss of the normal iliac flaring*

*Due to impaired growth of the cranial portion of the ilium. However, the change is much milder than that in achondroplasia and may not be present in older children.

● Shortening of the sciatic notches*

*Due to impaired growth of the caudal portion of the ilium. This is a useful finding; however, in some children with HCH, it is mild and difficult to recognize.

Long bones:

● Shortening of the femoral necks

● Apparent accentuation of metaphyseal flaring*

*The long bones are shortened, while the metaphyseal width is relatively preserved, which is thought to accentuate metaphyseal flaring.

● Squared appearance of the epiphyses*

*Said to be most easily recognized at the proximal tibia, although objective assessment can be difficult.

● Overgrowth of the distal fibula*

*Objective assessment can be difficult.

● Shortening of the distal ulna

● Overgrowth of the ulnar styloid process*

*Not helpful for diagnosis in younger children in whom the styloid process has not yet ossified.

Short tubular bones:

Clinically, many children have brachydactyly, but it is seldom possible to definitively confirm this on radiographs.

Cranial bones:

Shortening of the skull base, as observed in achondroplasia, is rarely observed. Mild frontal bossing can also be observed. Clinically, many children present with macrocephaly (Figs. 1 and 2).

Fig. 1.

Radiographs of a 6-yr-old child (A–C) and a 7-yr-old child (D) with achondroplasia (ACH), an 8-yr-old child with severe hypochondroplasia with FGFR3 [p.Tyr278Cys] (HCH #1) (E–H), an 8-yr-old child with typical hypochondroplasia with FGFR3 [p.Asn540Lys] (HCH #2) (I–L), and an 8-yr-old child with suspected precocious puberty (Control) (M–Q). The radiological hallmarks of achondroplasia include iliac hypoplasia (squared ilia with short greater sciatic notches and trident acetabula), narrow spinal canal (narrowing of the caudal interpedicular distances, bullet-shaped vertebral bodies with posterior scalloping, and short pedicles), proximal femoral scooping (short, constricted proximal femora), cupped metaphysis of the distal femora, and metaphyseal flaring of other long bones. Metaphyseal irregularities in the knee and ankle are not an essential finding of achondroplasia but are not uncommon. The fibulae are relatively elongated. The distal ulnae are hypoplastic. Severe brachydactyly is seen. Metacarpals show mild metaphyseal cupping. The growth plate is slanted in the metacarpals and proximal phalanges of the index and middle fingers. The severe hypochondroplasia phenotype is similar to achondroplasia. However, posterior scalloping of the vertebral bodies is absent, and the brachydactyly is milder. The long bones are unusually broad in this particular case. Typical hypochondroplasia manifests with less profound changes, i.e., mild iliac hypoplasia, spinal canal stenosis, and metaphyseal changes, which are readily identified as compared with the skeletal manifestation in suspected precocious puberty. For example, the interpediculate distances are caudally decreased in hypochondroplasia, while they are caudally increased in suspected precocious puberty.

Fig. 2.

Radiographs of achondroplasia (ACH) (A–D), typical hypochondroplasia with FGFR3 [p.Asn540Lys] (HCH) (E–H), and suspected premature thelarche (Control) (I–L) at 3 yr of age. These images help to understand the similarities and differences between achondroplasia and typical hypochondroplasia in early childhood. Hypochondroplasia presents with mild spondylar modifications, iliac hypoplasia, and metaphyseal flaring. Proximal femoral scooping is easy to recognize at a younger age.

Skeletal findings in fetuses, neonates, and infants

Although early reports included examples of neonatal and infant radiographs, they did not specifically discuss their characteristic features. Many descriptions emphasize that radiographic diagnosis at a young age is challenging. However, advancements in prenatal diagnosis since the 1990s and the proliferation of genetic diagnosis since the 2000s have led to the recognition that diagnosis is feasible during both neonatal and fetal periods (11, 12). A scoring system based on measurements from neonatal radiographs has also been proposed (13). The diagnostic findings were as follows.

Spine:

● Delayed ossification of the vertebral bodies, which are rounded rather than rectangular

● Loss of the normal progressive increase in interpedicular distance in the caudal lumbar spine and shortening of the pedicles*

*These findings may be mild and not apparent in some children with HCH.

Pelvis:

● Squaring of the iliac bones and shortening of the sciatic notches*

*Contrary to earlier descriptions, these changes are easier to recognize in neonates and infants than in older children.

Long bones:

● Band-like radiolucent zone in the femoral necks*

*This change, also observed in achondroplasia, is referred to as “scooping.” This results from the posterior concavity of the proximal femur. It is best seen on frontal radiographs but can often be recognized even when the femur is abducted and externally rotated. This phenomenon can sometimes be observed in early childhood. In early childhood, the femoral neck may appear not only short but also slightly slender.

● Apparent accentuation of metaphyseal flaring*

*Objective confirmation is likely if measurements are taken; however, visual assessment is difficult. Subject to positional variation at the time of radiography ( Fig. 3).

Fig. 3.

Radiographs of achondroplasia (ACH) (A–D), typical hypochondroplasia with FGFR3 [p.Asn540Lys] (HCH) (E–H), and transient tachypnea (Control) (I–L) in neonates. Both achondroplasia and hypochondroplasia share iliac hypoplasia, proximal femoral scooping, and vertebral deformities; however, these changes are more pronounced in achondroplasia.

Diagnosis

Diagnosis is established based on clinical manifestations and radiographic findings. However, as previously noted, these findings are often significantly milder than those observed in achondroplasia, making some individuals challenging to diagnose (1). While common genetic variants are present, substantial genetic heterogeneity results in a wide spectrum of patient phenotypes. Severe individuals with HCH resemble achondroplasia, while mild individuals may be diagnosed with constitutional short stature (3). The identification of a heterozygous pathogenic FGFR3 variant associated with HCH confirms this diagnosis (2,3,4,5,6,7). Collectively, these factors indicate that the accuracy of the clinical diagnosis of HCH based solely on clinical features and radiographic findings is sometimes challenging; therefore, the diagnosis of HCH is best confirmed through FGFR3 genetic testing. As of December 2025, FGFR3 genetic testing for HCH has not been covered by public health insurance in Japan. However, it is covered by insurance for achondroplasia in Japan. The testing data are available at the Kazusa DNA Research Institute, Kazusa Genetic Laboratory (https://www.genetest.jp/test_search.html).

Conflict of interests

Takuo Kubota has received consulting fees and lecture fees from Kyowa Kirin and grants from BioMarin and Kyowa Kirin. Yasuhisa Ohata has received research funding from BioMarin Pharmaceutical Japan and Alexion, scholarship donations from Novo Nordisk Inc. and JCR Pharmaceuticals Co Ltd., and others from BioMarin Pharmaceutical Japan, Kyowa Kirin Co Ltd., JCR Pharmaceuticals Co Ltd., Novo Nordisk Inc., Pfizer Inc., and Alexion. Keita Okada has received honoraria from BioMarin Pharmaceuticals. Sumito Dateki has received honoraria from JCR Pharma, Novo Nordisk, and Pfizer. Noriyuki Namba has received lecture fees from Kyowa Kirin. Keiichi Ozono has received lecture fees from Kyowa Kirin. Toshimi Michigami has received honoraria from Alexion Pharmaceuticals Inc., Kyowa Kirin Co., Ltd., and BioMarin Pharmaceutical. Gen Nishimura, Hiroshi Kitoh, Tsuyoshi Isojima, Kosei Hasegawa, Ikuma Fujiwara, and Masaki Matsushita declare no conflicts of interest.

Funding Statement

This work was partly supported by a grant for Research on Measures for Intractable Diseases from the Japanese Ministry of Health, Labour, and Welfare (Grant Number: 25FC1011).