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Hypochondroplasia

Hypochondroplasia Syndrome

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.

Short Stature
  • It is difficult to establish whether the Ile538Val substitution is rare in hypochondroplasia patients or whether the individuals, who have a moderate degree of short stature, rarely seek medical help for the short stature and consequently are rarely diagnosed[ncbi.nlm.nih.gov]
  • If reduced growth or a short stature is revealed, radiological studies should be employed.[symptoma.com]
  • Abstract Hypochondroplasia, a heterogeneous and usually mild form of chondrodystrophy, is a common cause of short stature. It often goes unrecognized in childhood and is diagnosed in adult life when disproportionate short stature becomes obvious.[ncbi.nlm.nih.gov]
  • Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are[ncbi.nlm.nih.gov]
  • The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. DESIGN: This was a longitudinal cohort study.[ncbi.nlm.nih.gov]
Short Finger
  • fingers; the face is normal in appearance. hy·po·chon·dro·pla·si·a ( hī'pō-kon'drō-plā'zē-ă ), [MIM*146000] A skeletal dysplasia characterized by dwarfism with features similar to but much milder than achondroplasia; the cranium and facies are normal[medical-dictionary.thefreedictionary.com]
  • It is characterized by rhizomelic dwarfism, trident hands and short fingers, midface hypoplasia with macrocephaly and frontal bossing.[ctgt.net]
  • fingers and toes; broad hands Large head Bowed legs Decreased muscle tone Loose joints, limited motion range of the joints Some features may be visible only after the baby completes his/her childhood development phase.[dovemed.com]
Hyperkeratosis
  • Acanthosis nigricans (AN) is a velvety and papillomatous pigmented hyperkeratosis of the skin, which has been recognized in some genetic disorders more severe than HCH involving the FGFR3 gene.[ncbi.nlm.nih.gov]
  • 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[symptoma.com]
  • AN is a velvety and papillomatous pigmented hyperkeratosis of the skin, which appears mainly on the flexures and neck.[eje.bioscientifica.com]
Skin Lesion
  • Other skin lesions were frequently reported: café-au-lait macules, melanocytic nevi, lentigines, and seborrheic keratosis. The Lys650Thr mutation was the predominant reported mutation of FGFR3.[ncbi.nlm.nih.gov]
  • We review the present literature, describing studies in which FGFR3 mutations have been investigated in skin lesions: primarily seborrheic keratoses and epidermal nevi, but also other benign skin tumors and a single case of a squamous cell carcinoma.[ncbi.nlm.nih.gov]
  • Taken together, these three reports argue against a simple model in which kinase activity of the FGFR3 mutant form explains the severity of the manifestations, being skeletal defects or skin lesions.[eje.bioscientifica.com]
Skin Lesion
  • Other skin lesions were frequently reported: café-au-lait macules, melanocytic nevi, lentigines, and seborrheic keratosis. The Lys650Thr mutation was the predominant reported mutation of FGFR3.[ncbi.nlm.nih.gov]
  • We review the present literature, describing studies in which FGFR3 mutations have been investigated in skin lesions: primarily seborrheic keratoses and epidermal nevi, but also other benign skin tumors and a single case of a squamous cell carcinoma.[ncbi.nlm.nih.gov]
  • Taken together, these three reports argue against a simple model in which kinase activity of the FGFR3 mutant form explains the severity of the manifestations, being skeletal defects or skin lesions.[eje.bioscientifica.com]
Lordosis
  • Early recognition of this disorder is possible from the abnormal body proportions with short limbs and lumbar lordosis without facial stigmata of achondroplasia. Radiological confirmation is possible provided a full skeletal survey is made.[ncbi.nlm.nih.gov]
  • Hypochondroplasia (HCH) is an autosomal dominant skeletal dysplasia characterized by short extremities, short stature and lumbar lordosis, usually exhibiting a phenotype similar to but milder than achondroplasia (ACH).[ncbi.nlm.nih.gov]
  • Hypochondroplasia (HCP) is an autosomal dominant skeletal dysplasia characterized by short extremities, short stature and lumbar lordosis, usually exhibiting a phenotype similar to but milder than achondroplasia (ACP).[ncbi.nlm.nih.gov]
  • Abstract Hypochondroplasia (HCH) is an autosomal dominant condition characterised by short stature, micromelia, and lumbar lordosis.[ncbi.nlm.nih.gov]
  • The patients are normal at birth and in early childhood present with short-limbed dwarfism, thick body build, long trunk, normal head, moderate lumbar lordosis and broad, stubby hands and feet.[ncbi.nlm.nih.gov]
Macrocephaly
  • Although similar in phenotype to the patients without the mutation, they showed in addition relative macrocephaly.[ncbi.nlm.nih.gov]
  • Prenatal sonographic examinations performed at 32 and 35 weeks' gestation revealed a rhizomelic shortness of the long bones (femur and humerus) with macrocephaly.[ncbi.nlm.nih.gov]
  • Abstract Achondroplasia (ACH) is a frequent condition of unknown origin characterized by short-limbed dwarfism and macrocephaly.[ncbi.nlm.nih.gov]
  • By contrast, in the three pedigrees inconsistent with linkage to chromosome 4p16.3, the clinical phenotype was milder, macrocephaly and shortening of the long bones was less obvious, the hands were normal, and no metaphyseal flaring was noted.[ncbi.nlm.nih.gov]
  • She was subsequently diagnosed with hypochondroplasia at the age of 6 years when disproportional short stature, stocky habitus and macrocephaly were observed.[ncbi.nlm.nih.gov]
Short Arm
  • We report a child who presented with short stature, a relatively long trunk, short legs, short arm span, radiographic evidence of HCP and mild mental retardation. Genetic analysis revealed a heterozygous 1620C G (Asn540Lys) mutation in FGFR3.[ncbi.nlm.nih.gov]
  • Abstract Hypochondroplasia (HCH) is a skeletal dysplasia characterized by short stature with disproportionately short arms and legs. Anthopometrics and skeletal features are very similar to achondroplasia but milder.[ncbi.nlm.nih.gov]
  • Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly.[ncbi.nlm.nih.gov]
  • Hypochondroplasia (HCH) is also characterized by short stature with disproportionately short arms and legs. The skeletal features are very similar to Achondroplasia but usually tend to be milder.[sickkids.ca]
  • CLINICAL CHARACTERISTICS: Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly.[ncbi.nlm.nih.gov]
Short Hands
  • Reviewing the clinical and radiological manifestations of the disease a posteriori, we observed that the N540K mutation was associated with relative macrocrania with a high and large forehead and short hands.[ncbi.nlm.nih.gov]
  • Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly.[ncbi.nlm.nih.gov]
  • CLINICAL CHARACTERISTICS: Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly.[ncbi.nlm.nih.gov]
  • People with hypochondroplasia have short arms and legs and broad, short hands and feet. Other characteristic features include a large head, limited range of motion at the elbows, a sway of the lower back ( lordosis ), and bowed legs.[ghr.nlm.nih.gov]
  • Shortened Limbs Broad, short hands and feet Large head Limited range of motion in the elbow Sway of the lower back ( lordosis ) Bowed legs Small percentage have mild to moderate learning problems *Please be aware, not all of the characteristics may be[littlepeopleuk.org]
Brachydactyly
  • The following are characteristics consistent with this condition: Brachydactyly Short stature Micromelia Skeletal dysplasia Abnormality of femur Hypochondroplasia is transmitted as an autosomal dominant trait affecting the FGFR3 gene on chromosome 4p16.3[en.wikipedia.org]
  • After delivery, the fetus had short limbs, a narrow thorax, brachydactyly, and relative macrocephaly. Cytogenetic analysis of cultured placental cells revealed a karyotype of 46,XX.[ncbi.nlm.nih.gov]
  • 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[symptoma.com]
  • Radiologic features Shortening of long bones with mild metaphyseal flare (especially femora and tibiae) Narrowing of or failure to widen in the inferior lumbar interpedicular distances Mild to moderate brachydactyly Short, broad femoral neck Squared[slideshare.net]
Distractibility
  • A uniform method of callus distraction (callotasis) was used in all cases, although the order of lengthening of each bone differed among the cases.[ncbi.nlm.nih.gov]
  • BACKGROUND: Longer treatment period in distraction osteogenesis (DO) of the lower extremity leads to more frequent complications.[ncbi.nlm.nih.gov]
  • ( 18583390 ) Castro-FeijA o L....Pombo M. 2008 43 Clinical hypochondroplasia in a family caused by a heterozygous double mutation in FGFR3 encoding GLY380LYS. ( 17256796 ) Santos H.G....Wilkie A. 2007 44 Distraction osteogenesis of the lower extremity[malacards.org]
Withdrawn
  • After a definite diagnosis was achieved, pamidronate was withdrawn at the age of 28 months. No adverse events were observed during pamidronate therapy.[ncbi.nlm.nih.gov]
Frontal Bossing
  • The patient was born by cesarean section at 38 weeks of gestation and had rhizomelic shortness of the upper and lower limbs with excess skin folds, large head, enlarged fontanelles, frontal bossing, lumbar gibbus, trident position of the fingers, and[ncbi.nlm.nih.gov]
  • It is characterized by rhizomelic dwarfism, trident hands and short fingers, midface hypoplasia with macrocephaly and frontal bossing.[ctgt.net]
  • She has a flattened nasal bridge and mild frontal bossing. I don't really have a question at the end of this novel ... I'm just looking for advice and more information.[dailystrength.org]
  • In addition to the obvious limb deformities of short stature and bowing, children with achondroplasia typically have frontal bossing (prominent forehead), midface hypoplasia (upper jaw, cheekbones, and eye sockets have not grown as much as the rest of[paleyinstitute.org]
Focal Seizure
  • The patient had normal psychomotor development and showed early-onset focal seizures with left temporal localization on interictal and ictal electroencephalograph.[ncbi.nlm.nih.gov]

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].

Shortened Long Bone
  • The criteria for hypochondroplasia were disproportionate short stature and radiological evidence of shortened long bones and decrease or absence of normal increase in interpedicular distances of the lumbar column.[ncbi.nlm.nih.gov]

Treatment

  • Height SDS (H-SDS) and height velocity SDS (HV-SDS) using the standard for ACH significantly improved during three-year treatment as compared with that before treatment in both ACH and HCH except HV-SDS in the third year.[ncbi.nlm.nih.gov]
  • No treatment-related serious adverse events were reported. CONCLUSIONS: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early.[ncbi.nlm.nih.gov]
  • Their response to r-hGH treatment is significantly different (P less than 0.01).[ncbi.nlm.nih.gov]
  • Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P 0·05).[ncbi.nlm.nih.gov]
  • Management and treatment Treatment is symptomatic only. Prognosis Final adult height varies between 132 and 147 cm and life expectancy is normal. The documents contained in this web site are presented for information purposes only.[orpha.net]

Prognosis

  • Prognosis Final adult height varies between 132 and 147 cm and life expectancy is normal. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • A longer period will be required to assess the effect of treatment on adult height prognosis.[ncbi.nlm.nih.gov]
  • Prognosis The prognosis for most people with hypochondroplasia is very good. In general, they have minimal medical problems, normal IQ, and most achieve success and have a long life regardless of their stature.[encyclopedia.com]

Etiology

  • Cloverleaf skull is a trilobar skull deformity which is etiologically and genetically heterogeneous and occurs in association with a number of disorders which result from mutations in the fibroblast growth factor receptor genes.[ncbi.nlm.nih.gov]
  • Although the probability of both germline mutations occurring in a single individual is exceedingly low, the etiology and mechanism are unknown in this patient.[ncbi.nlm.nih.gov]
  • Etiology The disorder is caused by mutations in the fibroblast growth factor receptor-3 gene ( FGFR3 ; 4p16.3).[orpha.net]
  • Advances in understanding etiology of achondroplasia and review of management. Curr Opin Pediatr 2007;19:32–7. PubMed Crossref Google Scholar 4. Aksu G, Genel F, Koturoğlu G, Kurugöl Z, Kütükçüler N.[degruyter.com]

Epidemiology

  • Summary Epidemiology Prevalence is estimated at around 1 in 33,000. Clinical description The clinical manifestations generally become apparent during childhood. Bowlegs may also be present.[orpha.net]
  • Chiara University Hospital of Pisa, Pisa, Italy. 2 Epidemiology Unit, Department of Experimental Pathology M.B.I.E., University of Pisa, 56126 Pisa PI, Italy.[ncbi.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • The amino acid exchange itself most probably has no impact on the three-dimensional structure of the receptor domain, suggesting that the phenotype is the result of altered receptor glycosylation and its pathophysiological consequences.[ncbi.nlm.nih.gov]

Prevention

  • Medical care for individuals with skeletal dysplasia should be directed at preventing neurologic and orthopedic complications due to spinal cord compression, joint instability, and long bone deformity.[emedicine.medscape.com]
  • Hurlin, Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes, Human Molecular Genetics, 10.1093/hmg/ddu594, 24, 6, (1764-1773), (2014). Shannon G.[doi.org]
  • Prevention of Secondary Complications The following are appropriate: Standard management of frequent middle ear infections Consideration of surgery if neurologic status is affected by spinal cord compression Surveillance Height, weight, and head circumference[ncbi.nlm.nih.gov]

References

Article

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

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Last updated: 2019-07-11 21:32