RMRP Gene Research Articles

Identification of a founder effect involving n.197C>T variant in RMRP gene associated to cartilage-hair hypoplasia syndrome in Brazilian patients

Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder frequently linked to n.72A>G (previously known as n.70A>G and n.71A>G), the most common RMRP variant worldwide. More than 130 pathogenic variants in this gene have already been described associated with CHH, and founder alterations were reported in the Finnish and Japanese populations. Our previous study in Brazilian CHH patients showed a high prevalence of n.197C>T variant (former n.195C>T and n.196C>T) when compared to other populations. The aim of this study was to investigate a possible founder effect of the n.197C>T variant in the RMRP gene in a series of CHH Brazilian patients. We have selected four TAG SNPs within chromosome 9 and genotyped the probands and their parents (23 patients previously described and nine novel). A common haplotype to the n.197C>T variant carriers was identified. Patients were also characterized for 46 autosomal Ancestry Informative Markers (AIMs). European ancestry was the most prevalent (58%), followed by African (24%) and Native American (18%). Our results strengthen the hypothesis of a founder effect for the n.197C>T variant in Brazil and indicate that this variant in the RMRP gene originated from a single event on chromosome 9 with a possible European origin.

Clonal Hematopoiesis in Cartilage-Hair Hypoplasia

Background: Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder characterized by short stature, hypotrichosis, combined immunodeficiency, and macrocytic anemia. CHH is caused by germline mutations in the RMRP gene encoding the RNA component of the mitochondrial RNA processing endoribonuclease. CHH is heavily enriched in the Finnish (1 in 23000 births) and the Amish (1 in 1340 births) populations. Transient macrocytic anemia is common in children with CHH, whereas severe hypoplastic macrocytic anemia is only present in 10% of pediatric CHH patients and can be treated with allogeneic hematopoietic stem cell transplantation (HSCT). The mechanism behind hypoplastic anemia in CHH is unknown: while erythroid differentiation from hematopoietic stem cells is impaired in vitro in CHH, immune dysregulation may also play a role in this phenotype. Clonal hematopoiesis is a common phenomenon of aging. Patients with inherited and immune-mediated bone marrow failure (BMF) show distinct spectra of clonal hematopoiesis mutations, reflecting context-specific selection of hematopoietic stem cell clones. However, the spectrum of clonal hematopoiesis is yet to be characterized in CHH. Methods: To assess the landscape of somatic alterations in hematopoietic cells in CHH, we performed whole exome sequencing (WES) on twelve bone marrow samples of four pediatric (age 4 to 13 years) and eight adult (age 20 to 52 years) unrelated subjects with CHH. Three children with CHH had severe hypoplastic anemia at the time of DNA sampling and three patients underwent HSCT during follow-up. Seven adults with CHH had normal blood counts and no severe immune phenotypes despite other clinical manifestations of CHH. Matched skin fibroblast samples were available for five CHH adults in the cohort for whom we performed tumor-normal variant calling. For the remaining cases, variant calling was based on tumor-only samples and stringent filtering to exclude germline variants. Additionally, we queried the FINRISK dataset, a Finnish cohort comprising WES and SNP microarray data from 10 129 participants, for the presence of CHH associated RMRP variants and evaluated their association with clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs). Results: The median WES coverage of the bone marrow samples was 445x (347-505). Eleven out of 12 patients were homozygous for the RMRP founder variant n.71A>G and one patient was compound heterozygous for two pathogenic RMRP variants. We observed no somatic reversion of the germline RMRP variants. Two pediatric patients had variants in the CHIP genes: CHH1 (age 13 years) with TP53 hotspot variant R175C (variant allele frequency, VAF 0.006) and CHH2 (age 4 years) with BCORL1 P1681Qfs*20 (VAF 0.025). One fifty-year-old patient had a DNMT3A splicing variant c.1555-1G>C (VAF 0.022), likely consistent with CHIP observed in older general population. To identify clonal hematopoiesis outside the classical CHIP genes, we performed conservative filtering of the remaining somatic variant calls, resulting in a list of 36 high-confidence coding variants (VAF >0.02). These variants were present in 10 out of 12 patients; no recurrent genetic alterations were observed. Finally, the analysis of the FINRISK dataset revealed eleven participants with RMRP disease-associated variants; each participant had one heterozygous RMRP variant. No enrichment of CHIP variants or mCAs were observed in carriers of RMRP variants. Conclusion: We observed TP53 and BCORL1 mutations in the bone marrow samples of pediatric patients with CHH. In comparison to other CHIP-associated conditions, BCORL1 variants are disproportionately represented in immune-mediated aplastic anemia, potentially suggestive of similar immune-mediated origin of hypoplastic anemia in CHH. TP53 mutations are abundant in inherited BMF syndromes; however and in contrast to classical inherited BMF syndromes, CHH is not associated with increased risk of myeloid malignancies. No enrichment of classical or non-classical clonal hematopoiesis mutations were observed in adults with clinical CHH diagnosis or in RMRP variant carriers in the population-level FINRISK cohort. This is consistent with transient selection pressure on hematopoietic stem cells in childhood CHH. To our knowledge, our study is the first attempt to characterize the spectrum of clonal hematopoiesis in CHH.

Shorter birth length and decreased T-cell production and function predict severe infections in children with non–severe combined immunodeficiency cartilage–hair hypoplasia

Cartilage-hair hypoplasia (CHH) is a syndromic inborn error of immunity caused by variants in the RMRP gene. Disease manifestations vary, and their ability to predict outcome is uncertain. The optimal management of infants with CHH who do not fulfill classical severe combined immunodeficiency (SCID) criteria is unknown. We described longitudinal changes in lymphocyte counts during childhood and explored correlations of early childhood clinical and laboratory features with clinical outcomes on long-term follow-up of CHH patients. Immunologic laboratory parameters, birth length, the presence of Hirschsprung disease, and severe anemia correlated to the primary end points of respiratory and severe infections. We implemented traditional statistical methods and machine learning techniques. Thirty-two children with CHH were followed up for 2.7 to 22.1 years (median, 8.2 years, in total 331.3 patient-years). None of the patients had classical SCID. Median lymphocyte subclass counts, apart from CD16+/56+ cells, were subnormal throughout childhood, but did not show age-related decline seen in healthy children. Low immunoglobulin levels were uncommon and often transient. Respiratory and/or severe infections developed in 14 children, 8 of whom had low naive T-cell counts, absent T-cell receptor excision circles, and/or partial "leaky" SCID-level lymphopenia. Shorter birth length correlated with lower lymphocyte counts and the occurrence of infections. Of the laboratory parameters, decreased naive T-cell counts and abnormal lymphocyte proliferation responses contributed most to the development of severe infections. In addition, all participants with absent T-cell receptor excision circles developed severe infections. Opportunistic infections occurred only in children with leaky SCID-level lymphopenia. Shorter birth length and a combination of laboratory abnormalities can predict the development of severe infections in children with CHH.

Cartilage hair hypoplasia with severe combined immunodeficiency caused by a novel RMRP gene variant

1例合并重症联合免疫缺陷表现的软骨毛发发育不全患儿，临床主要表现为短肢矮小，干骺端发育不良，重症联合免疫缺陷以及骨髓造血衰竭。基因分析显示患儿RMRP基因存在新的复合杂合变异。该变异导致RMRP基因mRNA表达水平下降，可能引起细胞周期调控异常和端粒功能障碍。.

Clinical genetic characteristics of metaphyseal chondrodysplasia, McKusick type (cartilage-hair hypoplasia) in children caused by mutations in the RMRP gene: authors’ observations and literature review

Introduction. Metaphyseal chondrodysplasia, McKusick type (MCD) (OMIM: #250250) (cartilage-hair hypoplasia) is a rare, autosomal recessive disorder with main clinical manifestations including disproportionate short stature, hair thinning and hypotrichosis. Some patients with MCD develop cellular and humoral immunodeficiency, bronchiectases and Hirschsprung disease. Such patients have an increased risk of developing malignant tumors and hypoplastic anemia. MCD is one of the rare monogenic disorders caused by mutations in the RMRP gene encoding a non-coding RNA instead of a protein. So far, 123 pathogenic RMRP variants have been described. The evidence of clinical genetic correlations in patients with different types and localization of gene mutations will facilitate further understanding of pathogenetic mechanisms of the disorder and enable to predict the spectrum and severity of clinical symptoms in individual patients.Materials and methods. We present the first description of clinical genetic characteristics of two Russian patients with MCD caused by mutations in the RMRP gene, along with the comparison of our results with literature data. In both cases the diagnosis was confirmed by analyzing the RMRP gene sequence using the direct Sanger sequencing technique.Results. Analysis of specific clinical signs observed during clinical examination of our patients in comparison with those reported in literature has shown the presence of typical skeletal and extraskeletal manifestations suggestive of MCD. In Russian patients we found the major mutation previously described in the Amish and Finnish populations, n.71A>G, present in compound heterozygous state, along with two other mutations: in one patient with an earlier described n.80G>A mutation, and in the other — a newly detected n.76C>T mutation. All detected mutations were mapped to a highly conserved region of the first domain that plays a major role in the functioning of the endoribonuclease complex.Conclusions. Considering the small size of the RMRP gene and presence of specific signs of MCD, the most accurate and inexpensive method of molecular genetic analysis is the detection of mutations in the RMRP gene using direct automated Sanger sequencing. Timely diagnosis of MCD enables to choose the correct follow-up strategy for patients with this disorder.

Immunodeficiency in cartilage-hair hypoplasia: Pathogenesis, clinical course and management.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive syndromic immunodeficiency with skeletal dysplasia, short stature, hypotrichosis, variable degree of immune dysfunction and increased incidence of anaemia, Hirschsprung disease and malignancy. CHH is caused by variants in the RMRP gene, encoding the untranslated RNA molecule of the mitochondrial RNA-processing endoribonuclease, which participates in for example cell cycle regulation and telomere maintenance. Recent studies have expanded our understanding of the complex pathogenesis of CHH. Immune dysfunction has a major impact on clinical course and prognosis. Clinical features of immune dysfunction are highly variable, progressive and include infections, lung disease, immune dysregulation and malignancy. Mortality is increased compared with the general population, due to infections, malignancy and pulmonary disease. Several risk factors for early mortality have been reported in the Finnish CHH cohort and can be used to guide management. Newborn screening for severe combined immunodeficiency can possibly be of prognostic value in CHH. Regular follow-up by a multidisciplinary team should be implemented to address immune dysfunction in all patients with CHH, also in asymptomatic cases. Haematopoietic stem cell transplantation can cure immune dysfunction, but its benefits in mildly symptomatic patients with CHH remain debatable. Further research is needed to understand the mechanisms behind the variability of clinical features, to search for potential molecular treatment targets, to examine and validate risk factors for early mortality outside the Finnish CHH cohort and to develop management guidelines. This review focuses on the pathogenesis, clinical course and management of CHH.

Identification of Novel and Recurrent RMRP Variants in a Series of Brazilian Patients with Cartilage-Hair Hypoplasia: McKusick Syndrome

Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder caused by pathogenic variants of the RMRP gene and characterized by metaphyseal bone dysplasia associated with hypotrichosis, immunodeficiency, and predisposition to malignancy. However, the genotype-phenotype correlation in CHH is not well understood. Here, we report a single country cohort of 23 Brazilian patients with clinical and radiological features consistent with CHH. We found 23 different pathogenic variants in the RMRP gene - 12 novel and 11 previously described in the literature. Interestingly, the most frequent Finnish pathogenic variant related to CHH (g.71A>G) was not found in our cohort. In contrast, more than 50% of the patients carried the rare g.196C>T variant suggesting a possible founder effect in the Brazilian population. In silico analysis showed that pathogenic variants occurred either in the regions conserved in mammalian species or within essential domains for the ribonucleoprotein complex. Pathogenicity prediction studies can improve the understanding of how these variants affect RNA.

NEWBORN SCREEN AND CHALLENGES IN DIAGNOSIS OF LEAKY SCID AND CARTILAGE HAIR HYPOPLASIA

Introduction Cartilage-hair hypoplasia (CHH) is a rare disorder of skeletal dysplasia with varying degrees of immunodeficiency. Diagnosis is clinical with affected individuals displaying disproportionately short limbs and fine sparse hair. Genetic analysis of the ribonuclease mitochondrial RNA processing gene (RMRP) is confirmatory. Case Description The patient is an ex-38-week male born to non-consanguineous parents of Mexican descent who is status post colostomy after failing to pass meconium due to Hirshprung Disease (HD). Newborn screen revealed TRECs of 1 and flow cytometry showed 446 CD3 cells with proportionally low naïve subset (180) and low recent thymic emigrants (110). Mitogen and CD3 stimulated lymphoproliferation were low normal. His SCID gene panel revealed a compound heterozygous mutation in the RMRP gene. Skeletal survey was unremarkable and he was non-dysmorphic. He was ultimately discharged home with climbing CD3 populations. At 6 months of age his CD3 count was 970 and he had protective vaccine titers to haemophilus influenza and tetanus after two doses of vaccines. Discussion This case represents a unique presentation of CHH given lack of skeletal dysplasia and classic hair findings. The diagnosis was not made clinically but rather by laboratory studies: initially with the results of the failed newborn screen and later by focused genetic testing. Importantly, this ribosomal defect is not found on whole exome sequencing. Unlike our patient, prior reports of CHH with HD describe severe immunodeficiency. In this case, reassessment and clinical vigilance are essential before moving forward with hematopoietic stem cell transplant. Cartilage-hair hypoplasia (CHH) is a rare disorder of skeletal dysplasia with varying degrees of immunodeficiency. Diagnosis is clinical with affected individuals displaying disproportionately short limbs and fine sparse hair. Genetic analysis of the ribonuclease mitochondrial RNA processing gene (RMRP) is confirmatory. The patient is an ex-38-week male born to non-consanguineous parents of Mexican descent who is status post colostomy after failing to pass meconium due to Hirshprung Disease (HD). Newborn screen revealed TRECs of 1 and flow cytometry showed 446 CD3 cells with proportionally low naïve subset (180) and low recent thymic emigrants (110). Mitogen and CD3 stimulated lymphoproliferation were low normal. His SCID gene panel revealed a compound heterozygous mutation in the RMRP gene. Skeletal survey was unremarkable and he was non-dysmorphic. He was ultimately discharged home with climbing CD3 populations. At 6 months of age his CD3 count was 970 and he had protective vaccine titers to haemophilus influenza and tetanus after two doses of vaccines. This case represents a unique presentation of CHH given lack of skeletal dysplasia and classic hair findings. The diagnosis was not made clinically but rather by laboratory studies: initially with the results of the failed newborn screen and later by focused genetic testing. Importantly, this ribosomal defect is not found on whole exome sequencing. Unlike our patient, prior reports of CHH with HD describe severe immunodeficiency. In this case, reassessment and clinical vigilance are essential before moving forward with hematopoietic stem cell transplant.

ABNORMAL TREC RESULTS ON THE OHIO NEWBORN SCREEN IN CHILDREN WITH CARTILAGE-HAIR HYPOPLASIA

Introduction While newborn screening (NBS) using T-cell receptor excision circle (TREC) analysis was introduced primarily to screen for severe combined immunodeficiency (SCID), it also identifies T-cell lymphopenia or low naive T-cell numbers due to other etiologies. Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder caused by mutations in the RMRP gene that result in short limbed skeletal dysplasia and a range of immunologic deficits involving both cellular and humoral immune function. The immune defect can range from minor abnormalities to a SCID phenotype. Methods We analyzed the NBS TREC results performed in Ohio between July 2013 and July 2018. We reviewed the results of the immunologic workup in patients with abnormal TREC results who were later confirmed to have CHH. Results A total of 693,706 unique infants had NBS performed between July 2013 and July 2018, with 192 (0.027%) having abnormal TREC results. Eight infants with abnormal TREC results were diagnosed with CHH. This included 6 cases of non-SCID T-cell lymphopenia and 2 children with SCID phenotypes. In the children with abnormal screening and a diagnosis of CHH, the absolute CD4 lymphocyte counts on initial immunophenotyping ranged from 76 – 757 cells/mm3 (median = 552 cells/mm3). The two CHH patients with SCID received bone marrow transplants. Conclusions CHH is a rare genetic disorder associated with widely varying levels of T-cell lymphopenia ranging from clinically insignificant to SCID. The T-cell lymphopenia may cause an abnormal result on the NBS TREC analysis, allowing for early diagnosis of a significant immunodeficiency and institution of life-saving therapies.

Wnt activated β-catenin and YAP proteins enhance the expression of non-coding RNA component of RNase MRP in colon cancer cells.

RMRP, the RNA component of mitochondrial RNA processing endoribonuclease, is a non-coding RNA (ncRNA) part of the RNase MRP complex functioning in mitochondrial and ribosomal RNA processing. Even though various mutations in the RMRP gene are linked to developmental defects and pathogenesis, its relevance to cancer etiology has not been well established. Here we examined the expression of RMRP and found a significant increase in colorectal and breast cancer patient tissues. So we tested whether the oncogenic signaling pathways, Wnt/β-catenin and Hippo/YAP pathways, are relevant to the enhanced expression of RMRP in cancer cells because of the predicted β-catenin/TCF and YAP/TBX5 elements in the upstream regions of the RMRP gene. As expected, Wnt signal activation significantly induced the RMRP transcription thru β-catenin and YAP transcription factors. More importantly, YAP protein was critical for RMRP transcription by association to the proximal site near the transcription start site of the RMRP gene, a Pol III promoter, along with β-catenin and TBX5 proteins. We propose that the interplay of Wnt and Hippo signaling pathways could regulate target genes, coding or non-coding, by the β-catenin/YAP/TBX5 transcription complex in cancer cells.

Cartilage–hair hypoplasia: a spectrum of clinical and radiological findings

Introduction: Cartilage–hair hypoplasia (CHH) is a rare skeletal dysplasia that presents with various degrees of immunodeficiency, short stature, and a susceptibility to malignancies. Individuals with CHH can present with severe combined immunodeficiency or combined immunodeficiency and are at risk for severe and unusual infections irrespective of their laboratory findings. In addition, individuals with CHH can present with variable skeletal abnormalities, mainly involving the metaphysis of long bones. CHH is a rare disease and familiarity with the variable features is crucial for diagnosis. Methods: We report the clinical, radiological, and genetic findings for 5 patients with proven diagnoses of CHH. Results: In this study we describe a cohort of patients with CHH and present their clinical findings and progressions. In addition, we present the radiological images and the immunological investigations that were done in these patients. Although all the patients in our cohort had poor cellular immunity, they had a variable clinical course. Three out of 5 patients received a bone marrow transplant (BMT) and 2 out of 5 died at an early age (1 after BMT). Those who had poor humoral function had a worse prognosis compared with those with good humoral function. The skeletal findings were characteristic for CHH. Conclusion: CHH is a disease with a variable presentation. Clinicians should be aware of the characteristic skeletal and immunological findings to identify the disease as early as possible. Statement of novelty: We present novel clinical and radiological findings in patients with variable RMRP gene mutations.

Cartilage hair hypoplasia: characteristics and orthopaedic manifestations.

PurposeCartilage hair hypoplasia (CHH) is a rare metaphyseal chondrodysplasia characterized by short stature and short limbs, found primarily in Amish and Finnish populations. Cartilage hair hypoplasia is caused by mutations in the RMRP gene located on chromosome 9p13.3. The disorder has several characteristic orthopaedic manifestations, including joint laxity, limited elbow extension, ankle varus, and genu varum. Immunodeficiency is of concern in most cases. Although patients exhibit orthopaedic problems, the orthopaedic literature on CHH patients is scant at best. The objective of this study was to characterize the orthopaedic manifestations of CHH based on the authors’ unique access to the largest collection of CHH patients ever reported.MethodsThe authors examined charts and/or radiographs in 135 cases of CHH. We analyzed the orthopaedic manifestations to better characterize and further understand the orthopaedic surgeon’s role in this disorder. In addition to describing the clinical characteristics, we report on our surgical experience in caring for CHH patients.ResultsGenu varum, with or without knee pain, is the most common reason a patient with CHH will seek orthopaedic consultation. Of the cases reviewed, 32 patients had undergone surgery, most commonly to correct genu varum.ConclusionThis paper characterizes the orthopaedic manifestations of CHH. Characterizing this condition in the orthopaedic literature will likely assist orthopaedic surgeons in establishing a correct diagnosis and appreciating the orthopaedic manifestations. It is important that the accompanying medical conditions are appreciated and evaluated.Electronic supplementary materialThe online version of this article (doi:10.1007/s11832-015-0646-z) contains supplementary material, which is available to authorized users.

Variable phenotype of severe immunodeficiencies associated with RMRP gene mutations.

Mutations in RMRP primarily give rise to Cartilage Hair Hypoplasia (CHH), a highly diverse skeletal disorder which can be associated with severe immunodeficiency. Increased availability of RMRP mutation screening has uncovered a number of infants with significant immunodeficiency but only mild or absent skeletal features. We surveyed the clinical and immunological phenotype of children who have undergone allogeneic haematopoietic stem cell transplantation for this condition in the UK. Thirteen patients with confirmed RMRP mutations underwent allogeneic stem cell transplantation (SCT) at two nationally commissioned centres using a variety of donors and conditioning regimens. Records were retrospectively reviewed. Median time from clinical presentation to diagnosis was 12 months (range 1 to 276 months), with three infants diagnosed with severe combined immunodeficiency (SCID) without radiographical manifestations of CHH. A total of 17 allogeneic procedures were performed on 13 patients including two stem-cell top-ups. The median age at transplant was 32.4 months (range 1.5 to 125 months). Of the eleven surviving patients, median follow-up was 50 months (range 21.6 to 168 months). RMRP mutations can cause short stature and significant immunodeficiency which can be corrected by allogeneic SCT and the diagnosis should be considered even in the absence of skeletal manifestations.

Treatment of cartilage–hair hypoplasia with recombinant human growth hormone

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder characterized by short stature, hypoplastic hair and humoral immunity disorders. It is a mutation in the RMRP gene, located on chromosome 9p13.3, that leads to CHH. There is no special treatment for short stature in CHH. The efficacy and safety of recombinant human growth hormone (rhGH) therapy in CHH is still under discussion. The present study describes the case of a girl with CHH who was treated with rhGH. The rhGH treatment had a significant effect on the height gain: the height SD score was changed from -4. to -2.98 after 4 years 7 months of treatment. rhGH therapy should be considered as a treatment modality for CHH, and insulin-like growth factor (IGF)-1 and IGF-binding protein 3 concentrations should be closely monitored, particularly because of the increased cancer risk that is a characteristic feature of CHH.

Foetal presentation of cartilage hair hypoplasia with extensive granulomatous inflammation

Cartilage-hair-hypoplasia is a rare autosomal recessive metaphyseal dysplasia due to RMRP (the RNA component of the RNase MRP ribonuclease mitochondrial RNA processing complex) gene mutations. So far, about 100 mutations have been reported in the promoter and the transcribed regions. Clinical characteristics include short-limbed short stature, sparse hair and defective cell-mediated immunity. We report herein the antenatal presentation of a female foetus, in whom CHH was suspected from 23 weeks' gestation, leading to a medical termination of the pregnancy at 34 weeks gestation, and thereafter confirmed by morphological and molecular studies. Post-mortem examination confirmed short stature and limbs, and revealed thymic hypoplasia associated with severe CD4 T-cell immunodeficiency along with extensive non caseating epithelioid granulomas in almost all organs, which to our knowledge has been described only in five cases. Molecular studies evidenced on one allele the most frequently reported founder mutation NR_003051: g.70A>G, which is present in 92% of Finnish patients with Cartilage Hair Hypoplasia. On the second allele, a novel mutation consisting of a 10 nucleotide insertion at position −18 of the promoter region of the RMRP gene (M29916.1:g.726_727insCTCACTACTC) was detected. The founder mutation was inherited from the father, and the novel mutation from the mother. To our knowledge, this case report represents the first detailed foetal analysis described in the literature.

Impaired fracture healing by highly selective COX-2 inhibition

Impaired fracture healing by highly selective COX-2 inhibition

Marked variability in the radiographic features of cartilage‐hair hypoplasia: Case report and review of the literature

Cartilage-hair hypoplasia (CHH) is a rare recessive metaphyseal chondrodysplasia characterized by severe short stature, ectodermal dysplasia, anemia in childhood, immune deficiency, susceptibility to malignancy, and normal intelligence. Short, thick long bones, metaphyseal flaring and irregularities, and globular epiphyses at the knees and ankles are the typical radiographic findings. The diagnosis is primarily made on the basis of clinical features, although mutations in the RMRP gene have recently been described in affected individuals, facilitating confirmation of the clinical diagnosis in atypical patients. We present a patient with two RMRP mutations whose stature and ectodermal features supported the diagnosis of CHH, but whose radiographic findings and other extraskeletal findings did not. We propose that the most consistent and reliable features of CHH are short stature of prenatal onset and ectodermal dysplasia, and suggest that the diagnosis of CHH be considered and mutation analysis pursued even when typical radiographic findings are absent.

Cartilage-hair hypoplasia caused by novel compound heterozygous RMRP mutations

Cartilage-hair hypoplasia is a rare, autosomal recessive skeletal dysplasia, caused by mutations in the RMRP gene. The skeletal abnormalities include irregular metaphyses and cone shaped epiphyses of the hands. Molecular diagnosis confirmed two novel RMRP mutations in a compound heterozygous state in two siblings with this condition.

An infant with cartilage-hair hypoplasia due to a novel homozygous mutation in the promoter region of theRMRP gene associated with chondrodysplasia and severe immunodeficiency

Cartilage-hair hypoplasia (CHH) is a rare autosomal-recessive disorder characterized by short-limbed dwarfism, sparse hair, and immune deficiency. It is caused by mutations in the RMRP gene, which encodes the RNA component of the mitochondrial RNA-processing ribonuclease (RNase MRP). Several mutations have been identified in its promoter region or transcribed sequence. However, homozygous mutations in the promoter region have been only reported in a patient with primary immunodeficiency without other features of CHH. We report on a Thai girl who first presented with chronic diarrhea, recurrent pneumonia, and severe failure to thrive, without apparently disproportionate dwarfism. The diagnosis of CHH was made after the severe wasting was corrected, and disproportionate growth became noticeable. The patient had the typical features of CHH, including sparse hair and metaphyseal abnormalities. The immunologic profiles were consistent with combined immune deficiency. Mutation analysis identified a novel homozygous mutation, g.-19_-25 dupACTACTC, in the promoter region of the RMRP gene. Identification of the mutation enabled us to provide a prenatal diagnosis in the subsequent pregnancy. This patient is the first CHH case with the characteristic features due to the homozygous mutation in the promoter region of the RMRP gene. The finding of severe immunodeficiency supports that promoter mutations markedly disrupt mRNA cleavage function, which causes cell-cycle impairment.

Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation

AbstractCartilage-hair hypoplasia (CHH) is a rare autosomal recessive disease caused by mutations in the RMRP gene. Beside dwarfism, CHH has a wide spectrum of clinical manifestations including variable grades of combined immunodeficiency, autoimmune complications, and malignancies. Previous reports in single CHH patients with significant immunodeficiencies have demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for the severe immunodeficiency, while growth failure remains unaffected. Because long-term experience in larger cohorts of CHH patients after HSCT is currently unreported, we performed a European collaborative survey reporting on 16 patients with CHH and immunodeficiency who underwent HSCT. Immune dysregulation, lymphoid malignancy, and autoimmunity were important features in this cohort. Thirteen patients were transplanted in early childhood (∼ 2.5 years). The other 3 patients were transplanted at adolescent age. Of 16 patients, 10 (62.5%) were long-term survivors, with a median follow-up of 7 years. T-lymphocyte numbers and function have normalized, and autoimmunity has resolved in all survivors. HSCT should be considered in CHH patients with severe immunodeficiency/autoimmunity, before the development of severe infections, major organ damage, or malignancy might jeopardize the outcome of HSCT and the quality of life in these patients.