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

  If reduced growth or a short stature is revealed, radiological studies should be employed. [symptoma.com]

  Children with the common C1620A mutation met all of the criteria for the diagnosis of Hch with a severe phenotype that resembled achondroplasia and disproportionate short stature in early childhood. [ncbi.nlm.nih.gov]

• Epilepsy

  Six of 13 patients had a history of seizures or epilepsy. Eight patients had undergone MRI. They all had structural abnormalities consistent with temporal lobe dysgenesis. [ncbi.nlm.nih.gov]

• Developmental Delay

  Further neuroimaging studies of patients with hypochondroplasia and epilepsy or developmental delay may clarify the proportion of patients with hypochondroplasia who have this pattern of central nervous system abnormalities. [ncbi.nlm.nih.gov]

  delay and acanthosis nigricans) Extremely short stature, profound developmental delay, marked tibial bowing, and acanthosis nigricans characterize this rare genetic disorder. [emedicine.medscape.com]

  Käytettävä termi Achondroplasia Tyyppi Topical Descriptor Ohjaustermit Achondroplasia, Severe, With Developmental Delay And Acanthosis Nigricans Käyttöhuomautus An autosomal dominant disorder that is the most frequent form of short-limb dwarfism. [finto.fi]

  It remains uncertain how the mutation causes developmental delay or acanthosis nigricans. [ghr.nlm.nih.gov]

• Short Finger

  broad and short 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 [medical-dictionary.thefreedictionary.com]

  It is characterized by rhizomelic dwarfism, trident hands and short fingers, midface hypoplasia with macrocephaly and frontal bossing. [ctgt.net]

  […] limbs, especially the upper limbs; short 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 [dovemed.com]

  Showing of 28 | 80%-99% of people have these symptoms Abnormal form of the vertebral bodies 0003312 Brachydactyly Short fingers or toes 0001156 Childhood onset short-limb short stature 0011405 Micromelia Smaller or shorter than typical limbs 0002983 Short [rarediseases.info.nih.gov]

• Skin Lesion

  In these patients, the AN lesions began in childhood, and they were extensive. These lesions were located on the torso, the abdomen, and the face, in addition to the typical skin fold sites. [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]

• 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]

• Keratosis

  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]

  It has been suggested that the mutations involved in seborrheic keratosis may be caused by exposure to ultraviolet (UV) light. [ghr.nlm.nih.gov]

  Monteagudo, Familial seborrhoeic keratosis associated with multiple ‘pure reticulated acanthomas’ and infundibulocystic basal cell carcinomas, British Journal of Dermatology, 177, 6, (1654-1663), (2017). [doi.org]

• Lordosis

  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]

  Disease Characteristics: HCH is a form of dwarfism resulting in short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. [saintfrancis.com]

• Short Arm

  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]

  Disease Characteristics: HCH is a form of dwarfism resulting in short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. [saintfrancis.com]

  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]

• Short Hands

  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]

  Disease Characteristics: HCH is a form of dwarfism resulting in short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. [saintfrancis.com]

  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

  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]

  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]

  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]

• 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]

  Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, GENU VARUM, and trident hand. [finto.fi]

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].

• Hyperinsulinemia

  Testing for hyperinsulinemia is essential, also if a gene mutation is confirmed. [ncbi.nlm.nih.gov]

  FGFR3 mutations and the skin: Report of a patient with a FGFR3 gene mutation, Acanthosis nigricans, hypochondroplasia and hyperinsulinemia and review of the literature. Dermatology, 220, 297–305. [link.springer.com]

  FGF receptor signaling and achondroplasia/hypochondroplasia]. ( 20890030 ) Tanaka H. 2010 38 FGFR3 mutations and the skin: report of a patient with a FGFR3 gene mutation, acanthosis nigricans, hypochondroplasia and hyperinsulinemia and review of the literature [malacards.org]

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]

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]

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 The disorder is caused by mutations in the fibroblast growth factor receptor-3 gene ( FGFR3 ; 4p16.3). [orpha.net]

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]

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]

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]

The discussion covers the phenotype spectrum, epidemiology, mode of inheritance, pathogenesis, and clinical profile of each condition, all of which is accompanied by a wealth of illustrations. [books.google.ro]

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]

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]

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.