Prenatal Diagnosis of Cartilage-Hair Hypoplasia: A Narrative Review

Catarina Portela Carvalho; Inês Alves; Carolina Lemos; Luís Guedes-Martins

doi:10.20344/amp.23497

Autores

Catarina Portela Carvalho Instituto de Ciências Biomédicas Abel Salazar (ICBAS). Universidade do Porto. Porto. https://orcid.org/0009-0005-4530-757X
Inês Alves National Association for Skeletal Dysplasias (ANDO Portugal). Évora. & Comprehensive Health Research Centre (CHRC). School of Health and Human Development. Universidade de Évora. Évora. https://orcid.org/0000-0001-8963-4736
Carolina Lemos National Association for Skeletal Dysplasias (ANDO Portugal). Évora. & Unit for Multidisciplinary Research in Biomedicine (UMIB). Instituto de Ciências Biomédicas Abel Salazar (ICBAS). Universidade do Porto. & Laboratory for Integrative and Translational Research in Population Health (ITR). Porto. https://orcid.org/0000-0001-9803-9584
Luís Guedes-Martins Instituto de Ciências Biomédicas Abel Salazar (ICBAS). Universidade do Porto. Porto. & Fetal Medicine Unit. Centro Materno Infantil do Norte. Porto. & Woman and Reproductive Medicine Department. Serviço de Obstetrícia. Unidade Local de Saúde de Santo António. Centro Materno Infantil do Norte. Porto. https://orcid.org/0000-0002-0491-0752

DOI:

https://doi.org/10.20344/amp.23497

Palavras-chave:

Cabelo, Diagnóstico Pré-natal, Osteocondrodisplasias

Resumo

A hipoplasia cartilagem-cabelo é uma displasia óssea rara, com hereditariedade autossómica recessiva. Embora seja particularmente prevalente nas populações finlandesa e Amish, verificam-se cada vez mais casos documentados noutras populações. A doença é causada por variantes patogénicas no gene RMRP. A apresentação clínica é muito variável e pode incluir baixa estatura com membros curtos, alterações metafisárias, hipotricose e imunodeficiência, entre outras manifestações. Alguns achados podem apresentar-se precocemente no período pré-natal e a avaliação ecográfica é, muitas vezes, a ferramenta que levanta suspeição para esta doença. O propósito desta revisão é sintetizar a literatura existente sobre o diagnóstico pré-natal da hipoplasia cartilagem-cabelo, focando-se na sua base molecular e no papel da imagem e dos testes genéticos. Foi realizada pesquisa na base de dados PubMed/MEDLINE usando os termos ‘Prenatal diagnosis’, ‘Cartilage-hair hypoplasia’, ‘Skeletal dysplasias’, ‘Osteochondrodysplasias’ e ‘RMRP mutation’. O diagnóstico pré-natal desta doença permanece um desafio, visto que os achados ecográficos podem coincidir com os de outras displasias ósseas, nomeadamente formas letais. A discussão incluiu também preditores de letalidade e o potencial dos testes moleculares. Uma abordagem estruturada na avaliação pré-natal desta patologia, combinada com aconselhamento genético atempado, pode permitir um diagnóstico mais precoce e auxiliar as famílias nas decisões reprodutivas. Dado os avanços recentes nas tecnologias reprodutivas e o potencial impacto que a hipoplasia cartilagem-cabelo pode ter nos indivíduos afetados, esta patologia deve ser ativamente considerada em estudos futuros que explorem o diagnóstico pré-natal das displasias esqueléticas.

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Referências

McKusick VA, Eldridge R, Hostetler JA, Ruangwit U, Egeland JA. Dwarfism in the Amish. ii. cartilage-hair hypoplasia. Bull Johns Hopkins Hosp. 1965;116:285-326.

Vakkilainen S, Taskinen M, Mäkitie O. Immunodeficiency in cartilage-hair hypoplasia: pathogenesis, clinical course and management. Scand J Immunol. 2020;92:e12913. DOI: https://doi.org/10.1111/sji.12913

Riley P, Weiner DS, Leighley B, Jonah D, Morton DH, Strauss KA, et al. Cartilage hair hypoplasia: characteristics and orthopaedic manifestations. J Child Orthop. 2015;9:145-52. DOI: https://doi.org/10.1007/s11832-015-0646-z

Mäkitie O, Vakkilainen S. Cartilage-hair hypoplasia - anauxetic dysplasia spectrum disorders. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews. Seattle: University of Washington; 2023.

Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A 2023;191:1164-209. DOI: https://doi.org/10.1002/ajmg.a.63132

Kwan A, Manning MA, Zollars LK, Hoyme HE. Marked variability in the radiographic features of cartilage-hair hypoplasia: case report and review of the literature. Am J Med Genet A. 2012;158A:2911-6. DOI: https://doi.org/10.1002/ajmg.a.35604

Hall CM, Liu B, Haworth A, Reed L, Pryce J, Mansour S. Early prenatal presentation of the cartilage-hair hypoplasia/anauxetic dysplasia spectrum of disorders mimicking recurrent thanatophoric dysplasia. Eur J Med Genet. 2021;64:104162. DOI: https://doi.org/10.1016/j.ejmg.2021.104162

Dungan JS, Emerson DS, Phillips OP, Shulman LP. Cartilage-hair hypoplasia syndrome: implications for prenatal diagnosis. Fetal Diagn Ther. 1996;11:398-401. DOI: https://doi.org/10.1159/000264353

Sulisalo T, Sillence D, Wilson M, Ryynänen M, Kaitila I. Early prenatal diagnosis of cartilage-hair hypoplasia (CHH) with polymorphic DNA markers. Prenat Diagn. 1995;15:135-40. DOI: https://doi.org/10.1002/pd.1970150205

Krstić N, Običan SG. Current landscape of prenatal genetic screening and testing. Birth Defects Res. 2020;112:321-31. DOI: https://doi.org/10.1002/bdr2.1598

Sun X, Zhang R, Liu M, Chen H, Chen L, Luo F, et al. RMRP mutation disrupts chondrogenesis and bone ossification in zebrafish model of cartilage-hair hypoplasia via enhanced wnt/β-catenin signaling. J Bone Miner Res. 2019;34:2101-16. DOI: https://doi.org/10.1002/jbmr.3820

Thiel CT, Rauch A. The molecular basis of the cartilage-hair hypoplasia-anauxetic dysplasia spectrum. Best Pract Res Clin Endocrinol Metab. 2011;25:131-42. DOI: https://doi.org/10.1016/j.beem.2010.08.004

Venturi G, Montanaro L. How altered ribosome production can cause or contribute to human disease: the spectrum of ribosomopathies. Cells. 2020;9:2300. DOI: https://doi.org/10.3390/cells9102300

Crahes M, Saugier-Veber P, Patrier S, Aziz M, Pirot N, Brasseur-Daudruy M, et al. Foetal presentation of cartilage hair hypoplasia with extensive granulomatous inflammation. Eur J Med Genet. 2013;56:365-70. DOI: https://doi.org/10.1016/j.ejmg.2013.04.004

Park JH, Im M, Kim YJ, Jang JH, Lee SM, Kim MS, et al. Cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders harboring RMRP mutations in two Korean children: a case report. Medicine. 2024;103:e37247. DOI: https://doi.org/10.1097/MD.0000000000037247

Kavadas FD, Giliani S, Gu Y, Mazzolari E, Bates A, Pegoiani E, et al. Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations. J Allergy Clin Immunol. 2008;122:1178-84. DOI: https://doi.org/10.1016/j.jaci.2008.07.036

Vatanavicharn N, Visitsunthorn N, Pho-iam T, Jirapongsananuruk O, Pacharn P, Chokephaibulkit K, et al. An infant with cartilage-hair hypoplasia due to a novel homozygous mutation in the promoter region of the RMRP gene associated with chondrodysplasia and severe immunodeficiency. J Appl Genet. 2010;51:523-8. DOI: https://doi.org/10.1007/BF03208884

Vakkilainen S, Skoog T, Einarsdottir E, Middleton A, Pekkinen M, Öhman T, et al. The human long non-coding RNA gene RMRP has pleiotropic effects and regulates cell-cycle progression at G2. Sci Rep. 2019;9:13758. DOI: https://doi.org/10.1038/s41598-019-50334-6

Savarirayan R, Rossiter JP, Hoover-Fong JE, Irving M, Bompadre V, Goldberg MJ, et al. Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia. Am J Obstet Gynecol. 2018;219:545-62. DOI: https://doi.org/10.1016/j.ajog.2018.07.017

Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med. 2009;11:127-33. DOI: https://doi.org/10.1097/GIM.0b013e3181971ccb

Milks KS, Hill LM, Hosseinzadeh K. Evaluating skeletal dysplasias on prenatal ultrasound: an emphasis on predicting lethality. Pediatr Radiol. 2017;47:134-45. DOI: https://doi.org/10.1007/s00247-016-3725-5

Lugli L, Ciancia S, Bertucci E, Lucaccioni L, Calabrese O, Madeo S, et al. Homozygous n.64C>T mutation in mitochondrial RNA-processing endoribonuclease gene causes cartilage hair hypoplasia syndrome in two siblings. Eur J Med Genet. 2021;64:104136. DOI: https://doi.org/10.1016/j.ejmg.2021.104136

Gamliel A, Lee Y, Lev A, AbuZaitun O, Rechavi E, Levy S, et al. Immunologic heterogeneity in 2 cartilage-hair hypoplasia patients with a distinct clinical course. J Investig Allergol Clin Immunol. 2023;33:263-70. DOI: https://doi.org/10.18176/jiaci.0792

Uchida N, Ishii T, Nishimura G, Sato T, Kuratsuji G, Nagasaki K, et al. RMRP-related short stature: a report of six additional Japanese individuals with cartilage hair hypoplasia and literature review. Am J Med Genet A. 2024;194:e63562. DOI: https://doi.org/10.1002/ajmg.a.63562

Berceanu C, Gheonea IA, Vlădăreanu S, Cîrstoiu MM, Vlădăreanu R, Mehedinţu C, et al. Ultrasound and MRI comprehensive approach in prenatal diagnosis of fetal osteochondrodysplasias. Cases series. Med Ultrason. 2017;19:66. DOI: https://doi.org/10.11152/mu-922

Gilligan LA, Calvo-Garcia MA, Weaver KN, Kline-Fath BM. Fetal magnetic resonance imaging of skeletal dysplasias. Pediatr Radiol. 2020;50:224-33. DOI: https://doi.org/10.1007/s00247-019-04537-8

Waratani M, Ito F, Tanaka Y, Mabuchi A, Mori T, Kitawaki J. Prenatal diagnosis of fetal skeletal dysplasia using 3-dimensional computed tomography: a prospective study. BMC Musculoskelet Disord. 2020;21:662. DOI: https://doi.org/10.1186/s12891-020-03663-x

Waratani M, Hasegawa T, Shimura K, Tanaka Y, Ito F, Takahata A, et al. Prenatal diagnosis of achondroplasia and hypochondroplasia using three-dimensional computed tomography: a case series at a single institution. Quant Imaging Med Surg. 2024;14:9543-51. DOI: https://doi.org/10.21037/qims-24-682

Cui L, Hu H, Zhai X, Qi M, Liu Y, Han C, et al. Analysis of a series of 26 cases with prenatal skeletal dysplasia via multiplatform genetic detection. Mol Genet Genomic Med. 2025;13:e70062. DOI: https://doi.org/10.1002/mgg3.70062

Jiang M, Zhang B, Wang J, Qiao W, Mao X, Yu B. Sequential prenatal diagnosis of fetal skeletal dysplasia: a cohort study. Acta Obstet Gynecol Scand. 2025;104:860-74. DOI: https://doi.org/10.1111/aogs.15095

Han J, Yang Y, He Y, Liu W, Zhen L, Pan M, et al. Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: benefit for prenatal counseling and pregnancy management. Prenat Diagn. 2020;40:577-84. DOI: https://doi.org/10.1002/pd.5653

Sirica R, Ottaiano A, D’Amore L, Ianniello M, Petrillo N, Ruggiero R, et al. Advancing non-invasive prenatal screening: a targeted 1069-gene panel for comprehensive detection of monogenic disorders and copy number variations. Genes. 2025;16:427. DOI: https://doi.org/10.3390/genes16040427

Chitty LS, Khalil A, Barrett AN, Pajkrt E, Griffin DR, Cole TJ. Safe, accurate, prenatal diagnosis of thanatophoric dysplasia using ultrasound and free fetal DNA. Prenat Diagn. 2013;33:416-23. DOI: https://doi.org/10.1002/pd.4066

Vivanti AJ, Costa JM, Rosefort A, Kleinfinger P, Lohmann L, Cordier AG, et al. Optimal non-invasive diagnosis of fetal achondroplasia combining ultrasonography with circulating cell-free fetal DNA analysis. Ultrasound Obstet Gynecol. 2019;53:87-94. DOI: https://doi.org/10.1002/uog.19018

Stembalska A, Dudarewicz L, Śmigiel R. Lethal and life-limiting skeletal dysplasias: selected prenatal issues. Adv Clin Exp Med. 2021;30:641-7. DOI: https://doi.org/10.17219/acem/134166

Liu Y, Wang L, Yang YK, Liang Y, Zhang TJ, Liang N, et al. Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases. Diagn Pathol. 2019;14:76. DOI: https://doi.org/10.1186/s13000-019-0853-x