Hypochondroplasia is a clinical entity characterized by a short stature and a range of skeletal malformations, occurring due to mutations in the fibroblast growth factor 3 gene, one of the key negative regulators of bone growth and development. A clinical suspicion must exist when typical signs and symptoms are observed, and radiologic, as well as genetic studies, are used to confirm the diagnosis.
Presentation
The clinical presentation of patients with hypochondroplasia (HCH), unlike other disorders involving the fibroblast growth factor 3 (FGF3) gene, such as achondroplasia, may be insidious, and rarely start during infancy and childhood [1] [2]. The cardinal manifestation of HCH is a short stature, ranging from severe dwarfism to only mild reductions [1] [2]. Shortening of the lower limbs, genu varum (bowing of the legs), an increased sitting height to standing height ratio, and a reduced growth rate is most frequently detected at the end of puberty when boys and girls fail to reach adequate height based on their previous growth rates [2]. Numerous features can accompany short stature - macrocephaly, a prominent forehead, brachydactyly involving both the hands and the feet, lumbar lordosis, and a limited range of joint motion (elbows are commonly affected) are frequent manifestations, with marked variations in terms of severity from patient to patient [1] [3]. Many individuals, however, remain undiagnosed for a significant period of time or are misdiagnosed as idiopathic short stature [2] [3]. Moreover, insulin resistance and the appearance of acanthosis nigricans, a papillomatous pigmented hyperkeratosis of the skin appearing on the flexures of the neck in most cases, which is strongly associated with FGF3-related disorders due to its role in pancreatic proliferation, is infrequently present in HCH patients [3] [4]. In some individuals, intellectual impairment may be noted.
Workup
Physicians can make a presumptive diagnosis of HCH only with a meticulously performed physical examination, as very subtle or mild skeletal changes are observed in the majority of patients. Assessment of growth rate, examination of the extremities, establishing body proportions and determination of joint mobility are mandatory parts of the physical examination. Having in mind that HCH is transferred through an autosomal dominant pattern of inheritance, patient history could potentially reveal similar findings in one of the parents, but many mutations arise de novo (sporadically) [3], and for this reason, the diagnosis should not be excluded in the absence of a positive family history. If reduced growth or a short stature is revealed, radiological studies should be employed [5]. Plain radiography of the spine, arms, and legs may reveal several key features - flared metaphyses, short femoral neck, square ilia and narrow interpedicular spaces [1]. A more concrete diagnosis can be made based on clinical and radiologic findings, but to confirm HCH as the underlying cause, genetic studies are the final step in the workup. Molecular analysis of FGF3 and detection of mutations involving this gene is detrimental [3].
Treatment
There is no cure for hypochondroplasia, but treatment focuses on managing symptoms and improving quality of life. Growth hormone therapy may be considered to increase height, although its effectiveness can vary. Physical therapy can help improve mobility and strength. In some cases, surgical procedures may be necessary to correct bone deformities or address spinal issues.
Prognosis
The prognosis for individuals with hypochondroplasia is generally good. Most people with the condition lead normal, healthy lives with a normal life expectancy. However, they may face challenges related to their short stature and potential orthopedic issues. Early intervention and supportive care can help mitigate these challenges and improve outcomes.
Etiology
Hypochondroplasia is caused by mutations in the FGFR3 gene, which provides instructions for making a protein involved in bone growth and development. These mutations lead to an overactive FGFR3 protein, which disrupts normal bone growth and results in the characteristic features of the condition. The disorder is typically inherited in an autosomal dominant pattern, meaning only one copy of the altered gene is needed to cause the condition.
Epidemiology
Hypochondroplasia is a rare condition, with an estimated prevalence of 1 in 15,000 to 40,000 individuals worldwide. It affects both males and females equally and occurs in all ethnic groups. Because the symptoms can be mild, some cases may go undiagnosed or be misdiagnosed as other forms of short stature.
Pathophysiology
The pathophysiology of hypochondroplasia involves the FGFR3 gene, which plays a crucial role in regulating bone growth. Mutations in this gene lead to an overactive receptor, which inhibits the proliferation and differentiation of chondrocytes—cells responsible for cartilage formation. This disruption in cartilage development affects the growth of long bones, resulting in the short stature and skeletal abnormalities seen in hypochondroplasia.
Prevention
Currently, there is no known way to prevent hypochondroplasia, as it is a genetic condition. Genetic counseling may be beneficial for families with a history of the disorder to understand the risks and implications of passing the condition to future generations. Prenatal testing can also be considered for at-risk pregnancies to determine if the fetus has inherited the condition.
Summary
Hypochondroplasia is a genetic disorder characterized by short stature and skeletal abnormalities due to mutations in the FGFR3 gene. While there is no cure, treatment focuses on managing symptoms and improving quality of life. The condition is rare but generally has a good prognosis, with most individuals leading normal lives. Understanding the genetic basis and potential complications can help in providing appropriate care and support.
Patient Information
For patients and families affected by hypochondroplasia, it is important to understand that the condition is a genetic disorder affecting bone growth. While it results in short stature, many individuals with hypochondroplasia live healthy, fulfilling lives. Treatment options are available to address specific symptoms and improve quality of life. Support from healthcare providers, including genetic counseling and physical therapy, can be valuable in managing the condition.
References
- Nagahara K, Harada Y, Futami T, Takagi M, Nishimura G, Hasegawa Y. A Japanese familial case of hypochondroplasia with a novel mutation in FGFR3. Clin Pediatr Endocrinol. 2016;25(3):103-106.
- Kaissi AA, Farr S, Ganger R, Hofstaetter JG, Klaushofer K, Grill F. Treatment of Varus Deformities of the Lower Limbs in Patients with Achondroplasia and Hypochondroplasia. Open Orthop J. 2013;7:33-39.
- Castro-Feijóo L, Loidi L, Vidal A, et al. Hypochondroplasia and Acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation in the fibroblast growth factor receptor 3 gene? Eur J Endocrinol. 2008;159(3):243-249.
- Mustafa M, Moghrabi N, Bin-Abbas B. Hypochondroplasia, Acanthosis Nigricans, and Insulin Resistance in a Child with FGFR3 Mutation: Is It Just an Association? Case Rep Endocrinol. 2014;2014:840492.
- Prinster C, Del Maschio M, Beluffi G, et al. Diagnosis of hypochondroplasia: the role of radiological interpretation. Italian Study Group for Hypochondroplasia. Pediatr Radiol. 2001;31(3):203-208.