The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (-1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10-nucleotide duplication at position -13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS -1.6 at 14 years and -3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations.
Objective: This retrospective cohort study aims to describe the genetic spectrum of fetal skeletal dysplasias detected in a Finnish patient cohort and the diagnostic yield of various analysis methods used. Method:A total of 121 pregnancies with prenatally suspected or diagnosed skeletal dysplasia were analyzed between 2013 and 2020. Clinical details and findings from genetic testing were collected.Results: Abnormal ultrasound triggered further testing in most cases. However, there were several cases with increased nuchal translucency and/or abnormal risk ratio in the first trimester combined screening as the initial finding. Further genetic testing was performed in 84/121 (69.4%) cases. A genetic diagnosis was confirmed in 36/84 (42.9%) cases. Half of the identified cases could be attributed to a founder mutation specific to the Finnish Disease Heritage, whereas the other half consisted of a variety of other genetic defects. Conclusion:In our patient cohort, the overall genetic spectrum of prenatally diagnosed skeletal dysplasias was wide. However, the impact of Finnish founder mutations was considerable, suggesting that the genetic spectrum of skeletal dysplasias may differ significantly between populations. This should be taken into consideration during the diagnostic process especially as initial ultrasound findings may be unspecific and the interpretation of ultrasound features is usually difficult. Key points What's already known about this topic?� Prenatal diagnosis of skeletal dysplasia is challenging and broader diagnostic methods have increased the diagnostic yield. In addition to well-described ultrasound findings, increased nuchal translucency and/or abnormal first trimester combined screening could indicate skeletal disease.Katri Rajala and Ellamaija Kasanen contributed equally to this work and should be considered as joint first authors.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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