Acanthosis nigricans in achondroplasia

Smid, Cory J.; Modaff, Peggy; Alade, Adekemi Yewande; Legare, Janet M.; Pauli, Richard M.

doi:10.1002/ajmg.a.40506

Cited by 12 publications

(7 citation statements)

References 46 publications

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“…Although BMI is not the best measure of true obesity in achondroplasia, it is the marker most available. Patients with achondroplasia are known to have a higher risk of acanthosis nigricans (Smid et al, 2018) and this combined with a lower rate of diabetes type 2 is likely related to the phenotypic spectrum associated with gain of function mutations in FGFR3 and not related to insulin resistance. Acanthosis nigricans is known to be associated with other FGFR3 mutations in SADDAN syndrome (Bellus et al, 1999) and patients with achondroplasia and hypochondroplasia have been shown not to have insulin insensitivity or hyperinsulinemia despite central obesity (Alatzoglou et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, Crouzon syndrome-acanthosis nigricans (Arnau-López et al, 2007) typically has the features that give it its name, but also has been described as having subtle achondroplasia-like radiographic characteristics (Schweitzer et al, 2001). This and other recent findings (e.g., Smid et al, 2018;Mannikam et al, 2018) suggest that any clinical feature of one FGFR3 gain of function disorder can be expected to arise at some, low, usually currently unknown frequency in any other FGFR3 gain of function disorder. The presence of an unusual head shape or unusual craniofacial features in an infant with achondroplasia should precipitate evaluation to assess for the presence of craniosynostosis, including computerized tomography with 3D reconstruction, or similar imaging.…”

Section: Craniosynostosis In Achondroplasiamentioning

confidence: 96%

Section: Diabetes Mellitusmentioning

confidence: 99%

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CLARITY: Co‐occurrences in achondroplasia—craniosynostosis, seizures, and decreased risk of diabetes mellitus

Legare

Pauli

Hecht

et al. 2021

American J of Med Genetics Pt A

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Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000–30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY—aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under‐recognized features associated with achondroplasia. Craniosynostosis was found to co‐occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1–7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Section: Craniosynostosis In Achondroplasiamentioning

confidence: 96%

Section: Diabetes Mellitusmentioning

confidence: 99%

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CLARITY: Co‐occurrences in achondroplasia—craniosynostosis, seizures, and decreased risk of diabetes mellitus

Legare

Pauli

Hecht

et al. 2021

American J of Med Genetics Pt A

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“…The patient presents with extensive acanthosis nigricans starting early childhood, with or without neurological impairments. The skin changes in acanthosis nigricans are usually progressive and usually seen as a long-term complication rather than a specific clinical feature of SADDAN [11]. Impairment in endochondral bone growth is similar to what is observed in thanatophoric dysplasia, and Type I may also be seen in a patient with SADDAN.…”

Section: Severe Achondroplasia With Developmental Delay and Acanthosi...mentioning

confidence: 93%

The Roles of Fibroblast Growth Factor Receptor 3 (FGFR3) in the Spectrum of Skeletal Dysplasia

Okikiade

Afolayan-Oloye

Agboola

et al. 2023

AIR

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The fibroblast growth factor receptor 3 (FGFR3) gene mutations were identified to be involved in the pathogenesis of most chondropathies. The FGFR3 gene encodes the FGFR3 receptor and is involved in the regulation of bone growth by limiting the ossification of long bones. Mutations of the FGFR3 gene result in abnormal cell proliferation and improper cartilage development. We aim to provide an overview of the roles of FGFR3 in skeletal dysplasia by highlighting the pathogenesis, clinical variants of skeletal dysplasia, diagnosis, and their management. Achondroplasia is the most common form of chondropathies, occurring in approximately 1 in 20,000-30,000 live births, and it is the most common form of genetic dwarfism. In over 80% of cases of achondroplasia, the mutation is sporadic, and only 20% are inherited autosomal dominant. Achondroplasia results from a point mutation in the gene encoding the transmembrane portion of FGFR3. Two viable base substitutions are identified in achondroplasia, including a point mutation of guanine substituted for adenine (c.1138G>A); this is identified in approximately 98% of the affected individuals, and transversion of guanine to cytosine (c.1138G>C). Hypochondroplasia is a milder form of chondropathies with an incidence between 1 in 33,000 and 1 in 47,000 live births. Missense mutations of FGFR3 (p.Asn540Lys) are isolated in tyrosine kinase domain I occurring in approximately 60% of cases, and missense mutation of FGFR3 (p.Lys650Asn) identified in the tyrosine kinase domain II of FGFR3. Thanatophoric dysplasia is the most lethal form of chondropathies, with neonatal fetal death secondary to pulmonary hypoplasia. In thanatophoric dysplasia, there is Lys650Met substitution in FGFR3 (Type I) with impairment of endochondral bone growth and a pathogenic variant of p.Lys650Glu substitution in FGFR3 (Type II). In addition, specific amino acid substitution in the FGFR3 gene (G380R) was identified to be associated with severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). The diagnosis of achondroplasias is routinely made from clinical presentations and radiological findings. FGFR3 molecular genetic testing is performed in children with atypical presentations. In addition, a pre-implantation genetic diagnosis should be available for parents pursuing in-vitro fertilization and embryo implantation procedures. Management of chondropathies includes symptomatic treatment with drugs, surgical intervention, and lifelong follow-up care. Different pharmacological options have been used, including those that directly block FGFR3 activation or regulate signalling pathways controlling chondrocyte proliferation and differentiation.

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“…Acanthosis nigricans is a less frequent symptom in patients with achondroplasia, but it still occurs in 10% of cases [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

Wrobel

Pach

Beń‐Skowronek

2021

IJMS

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Achondroplasia (ACH) is a disease caused by a missense mutation in the FGFR3 (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in humans. The treatment of ACH is necessary and urgent because untreated achondroplasia has many complications, both orthopedic and neurological, which ultimately lead to disability. This review presents the current and potential pharmacological treatments for achondroplasia, highlighting the advantages and disadvantages of all the drugs that have been demonstrated in human and animal studies in different stages of clinical trials. The article includes the potential impacts of drugs on achondroplasia symptoms other than short stature, including their effects on spinal canal stenosis, the narrowing of the foramen magnum and the proportionality of body structure. Addressing these effects could significantly improve the quality of life of patients, possibly reducing the frequency and necessity of hospitalization and painful surgical procedures, which are currently the only therapeutic options used. The criteria for a good drug for achondroplasia are best met by recombinant human growth hormone at present and will potentially be met by vosoritide in the future, while the rest of the drugs are in the early stages of clinical trials.

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Acanthosis nigricans in achondroplasia

Cited by 12 publications

References 46 publications

CLARITY: Co‐occurrences in achondroplasia—craniosynostosis, seizures, and decreased risk of diabetes mellitus

CLARITY: Co‐occurrences in achondroplasia—craniosynostosis, seizures, and decreased risk of diabetes mellitus

The Roles of Fibroblast Growth Factor Receptor 3 (FGFR3) in the Spectrum of Skeletal Dysplasia

Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

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