RESUMEN
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.
Asunto(s)
Efecto Fundador , Cabello , Enfermedad de Hirschsprung , Osteocondrodisplasias , Polimorfismo de Nucleótido Simple , Humanos , Brasil , Enfermedad de Hirschsprung/genética , Masculino , Osteocondrodisplasias/genética , Osteocondrodisplasias/congénito , Femenino , Cabello/anomalías , ARN Largo no Codificante/genética , Haplotipos , Enfermedades de Inmunodeficiencia Primaria/genética , Hipotricosis/genética , Cromosomas Humanos Par 9/genética , NiñoRESUMEN
RATIONALE: Cartilage-hair hypoplasia (CHH, OMIM # 250250) is a rare autosomal recessive disorder, which includes cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders. CHH-AD is caused by homozygous or compound heterozygous mutations in the RNA component of the mitochondrial RNA-processing Endoribonuclease (RMRP) gene. PATIENT CONCERNS: Here, we report 2 cases of Korean children with CHH-AD. DIAGNOSES: In the first case, the patient had metaphyseal dysplasia without hypotrichosis, diagnosed by whole exome sequencing (WES), and exhibited only skeletal dysplasia and lacked extraskeletal manifestations, such as hair hypoplasia and immunodeficiency. In the second case, the patient had skeletal dysplasia, hair hypoplasia, and immunodeficiency, which were identified by WES. INTERVENTIONS: The second case is the first CHH reported in Korea. The patients in both cases received regular immune and lung function checkups. OUTCOMES: Our cases suggest that children with extremely short stature from birth, with or without extraskeletal manifestations, should include CHH-AD as a differential diagnosis. LESSONS SUBSECTIONS: Clinical suspicion is the most important and RMRP sequencing should be considered for the diagnosis of CHH-AD.
Asunto(s)
Cabello , Enfermedad de Hirschsprung , Mutación , Osteocondrodisplasias , Humanos , República de Corea , Osteocondrodisplasias/genética , Osteocondrodisplasias/diagnóstico , Masculino , Femenino , Cabello/anomalías , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/diagnóstico , Enanismo/genética , Enanismo/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Hipotricosis/genética , Hipotricosis/diagnóstico , Secuenciación del Exoma , Lactante , Preescolar , Endorribonucleasas/genética , Niño , ARN Largo no CodificanteAsunto(s)
Cabello/anomalías , Enfermedad de Hirschsprung , Osteocondrodisplasias , Osteocondrodisplasias/congénito , Enfermedades de Inmunodeficiencia Primaria , ARN Largo no Codificante , Humanos , Osteocondrodisplasias/mortalidad , Osteocondrodisplasias/genética , Osteocondrodisplasias/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/mortalidad , Factores de Riesgo , Enfermedad de Hirschsprung/mortalidad , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/diagnóstico , Masculino , Femenino , Lactante , Preescolar , Hipotricosis/genética , Hipotricosis/diagnóstico , Hipotricosis/mortalidad , NiñoRESUMEN
BACKGROUND: Cartilage-hair hypoplasia (CHH) is a rare syndromic immunodeficiency with metaphyseal chondrodysplasia and increased risk of malignancy. In this cross-sectional observational study, we examined HPV status and oral microbiome in individuals with CHH. Oral brush samples were collected from 20 individuals with CHH (aged 5-59 years) and 41 controls (1-69 years). Alpha HPVs (43 types) were tested by nested PCR followed by bead-based probe hybridization. Separately, beta-, gamma-, mu- and nu- HPV types were investigated, and a genome-based bacterial microbiome sequencing was performed. RESULTS: We found a similar alpha HPV prevalence in individuals with CHH (45%) and controls (36%). The HPV types of individuals with CHH were HPV-16 (25%), 27, 28, and 78, and of controls HPV-3, 16 (21%), 27, and 61. Beta HPV positivity and combined beta/gamma/mu/nu prevalence was detected in 11% and 11% of individuals with CHH and in 5% and 3% of the controls, respectively. Individuals with CHH differed from the controls in bacterial microbiota diversity, richness, and in microbial composition. Individuals with CHH had lower abundance of species Mitsuokella sp000469545, Parascardovia denticolens, Propionibacterium acidifaciens, UMGS1907 sp004151455, Salinicola halophilus, Haemophilus_A paraphrohaemolyticus, Fusobacterium massiliense, and Veillonella parvula, and higher abundance of Slackia exigua. CONCLUSIONS: Individuals with CHH exhibit similar prevalence of HPV DNA but different bacterial microbiota on their oral mucosa compared to healthy controls. This may partly explain the previously observed high prevalence of oral diseases in CHH, and regular oral examination is warranted.
Asunto(s)
Cabello , Enfermedad de Hirschsprung , Microbiota , Osteocondrodisplasias , Infecciones por Papillomavirus , Enfermedades de Inmunodeficiencia Primaria , Humanos , Estudios Transversales , Cabello/anomalías , Virus del Papiloma Humano , Osteocondrodisplasias/genética , Osteocondrodisplasias/congénito , Infecciones por Papillomavirus/epidemiología , PrevalenciaRESUMEN
Cartilage hypoplasia syndrome is a primary immunodeficiency disease characterized by short stature, hypoplastic hair and a variable degree of immunodeficiency. Noninfectious cutaneous granulomas represent an uncommon yet well-recognized manifestation within the spectrum of primary immunodeficiency diseases. However, cutaneous granulomas as a manifestation of cartilage-hair hypoplasia syndrome, are extremely rare. We present a case of a middle-aged man with cartilage hypoplasia syndrome featuring cutaneous granulomas, manifesting as chronic, extensive and deep cutaneous ulcers. The patient was treated with anti-TNF-alpha adalimumab with partial improvement. Our case underscores the broad spectrum of clinical manifestations associated with cartilage hypoplasia syndrome and adds new evidence to the potential therapeutic efficacy of anti-TNF-alpha drugs in its treatment.
Asunto(s)
Adalimumab , Granuloma , Cabello , Osteocondrodisplasias , Enfermedades de Inmunodeficiencia Primaria , Úlcera Cutánea , Humanos , Masculino , Cabello/anomalías , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Adalimumab/uso terapéutico , Úlcera Cutánea/etiología , Úlcera Cutánea/tratamiento farmacológico , Granuloma/tratamiento farmacológico , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/congénito , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/diagnóstico , Persona de Mediana Edad , Hipotricosis/diagnósticoRESUMEN
Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset growth failure, metaphyseal dysplasia, hair hypoplasia, immunodeficiency, and other extraskeletal manifestations. Herein, we report six Japanese individuals with CHH from four families. All probands presented with moderate short stature with mild metaphyseal dysplasia or brachydactyly. One of them had hair hypoplasia and the other immunodeficiency. By contrast, the affected siblings of two families showed only mild short stature. We also reviewed all previously reported 13 Japanese individuals. No n.71A > G allele was detected. The proportions of Japanese versus Finnish individuals were 0% versus 70% for birth length < -2.0 SD, 84% versus 100% for metaphyseal dysplasia and 26% versus 88% for hair hypoplasia. Milder manifestations in the Japanese individuals may be related to the difference of genotypes. The mildest form of CHH phenotypes is mild short stature without overt skeletal alteration or extraskeletal manifestation and can be termed "RMRP-related short stature".
Asunto(s)
Cabello , Osteocondrodisplasias , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Alelos , Enanismo/genética , Enanismo/patología , Pueblos del Este de Asia , Genotipo , Cabello/anomalías , Cabello/patología , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Enfermedad de Hirschsprung/diagnóstico , Japón/epidemiología , Mutación/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Osteocondrodisplasias/congénito , Linaje , Fenotipo , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/patología , ARN Largo no Codificante/genéticaRESUMEN
Uncombable hair syndrome is a rare hair shaft anomaly presenting in childhood with blond, frizzy, and unruly hair. This case report presents a 9-year-old boy with remarkable hair where the mother, after reading a medical paper on hair shaft anomalies, suspected uncombable hair syndrome. She reached out to the author group, and the employment of molecular genetics later confirmed the diagnosis of uncombable hair syndrome. This case report serves as an example of how digital access enables the attention of patients and relatives to be directed towards rare conditions.
Asunto(s)
Enfermedades del Cabello , Niño , Humanos , Masculino , Cabello/anomalías , Enfermedades del Cabello/diagnóstico , Madres , Cuidados PaliativosAsunto(s)
Enfermedad de Hirschsprung , Síndromes de Inmunodeficiencia , Osteocondrodisplasias , Enfermedades de Inmunodeficiencia Primaria , Humanos , Pueblos del Este de Asia , Cabello/anomalías , Enfermedad de Hirschsprung/diagnóstico , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , HermanosAsunto(s)
Enfermedad de Hirschsprung , Osteocondrodisplasias , Enfermedades de Inmunodeficiencia Primaria , ARN Largo no Codificante , Humanos , Enfermedades de Inmunodeficiencia Primaria/genética , Cabello/anomalías , Regiones Promotoras Genéticas , Enfermedad de Hirschsprung/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Cartílago , MutaciónRESUMEN
Introduction: Cartilage-hair hypoplasia (CHH) syndrome is a rare autosomal recessive syndrome associated with skeletal dysplasia, varying degrees of combined immunodeficiency (CID), short stature, hair hypoplasia, macrocytic anemia, increased risk of malignancies, and Hirschsprung disease. Purpose: To provide clinical and immunological insights obtained from 2 unrelated patients who displayed clinical characteristics of CHH. Methods: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency underwent an immunological and genetic work-up using flow cytometry, next-generation sequencing (NGS) of the immune repertoire, and Sanger sequencing to identify the underlying defects. Results: Patient 1 presented with low birth weight and skeletal dysplasia. Newborn screening was suggestive of T-cell immunodeficiency, as T-cell receptor excision circle levels were undetectable. Both the T-cell receptor (TCR) Vß and TCR-g (TRG) repertoires were restricted, with evidence of clonal expansion. Genetic analysis identified compound heterozygous RMRP variants inherited from both parents. Patient 2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive, and hepatomegaly. The polyclonal pattern of the TCRß repertoire was normal, with only slight overexpression of TCR-ßV20 and restricted expression of Vßs. TRG expressed a normal diverse repertoire, similar to that of the healthy control sample. Genetic analysis identified biallelic novel regulatory variants in RMRP. Both parents are carriers of this mutation. Conclusion: Our findings demonstrate how the immunological work-up, supported by genetic findings, can dramatically change treatment and future outcome in patients with the same clinical syndrome (AU)
Asunto(s)
Humanos , Recién Nacido , Lactante , Enfermedad de Hirschsprung , Síndromes de Inmunodeficiencia/genética , Progresión de la Enfermedad , Cabello/anomalías , Cabello/patología , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: Cartilage-hair hypoplasia (CHH) syndrome is a rare autosomal recessive syndrome associated with skeletal dysplasia, varying degrees of combined immunodeficiency (CID), short stature, hair hypoplasia, macrocytic anemia, increased risk of malignancies, and Hirschsprung disease. To provide clinical and immunological insights obtained from 2 unrelated patients who displayed clinical characteristics of CHH. METHODS: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency underwent an immunological and genetic work-up using flow cytometry, next-generation sequencing (NGS) of the immune repertoire, and Sanger sequencing to identify the underlying defects. RESULTS: Patient 1 presented with low birth weight and skeletal dysplasia. Newborn screening was suggestive of T-cell immunodeficiency, as T-cell receptor excision circle levels were undetectable. Both the T-cell receptor (TCR) Vß and TCR-g (TRG) repertoires were restricted, with evidence of clonal expansion. Genetic analysis identified compound heterozygous RMRP variants inherited from both parents. Patient 2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive, and hepatomegaly. The polyclonal pattern of the TCRß repertoire was normal, with only slight overexpression of TCR-ßV20 and restricted expression of Vßs. TRG expressed a normal diverse repertoire, similar to that of the healthy control sample. Genetic analysis identified biallelic novel regulatory variants in RMRP. Both parents are carriers of this mutation. CONCLUSION: Our findings demonstrate how the immunological work-up, supported by genetic findings, can dramatically change treatment and future outcome in patients with the same clinical syndrome.
Asunto(s)
Enfermedad de Hirschsprung , Síndromes de Inmunodeficiencia , Recién Nacido , Humanos , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/patología , Síndromes de Inmunodeficiencia/genética , Cabello/anomalías , Cabello/patología , Receptores de Antígenos de Linfocitos T/genética , Progresión de la EnfermedadRESUMEN
Background: Patients with cartilage-hair hypoplasia (CHH) have an increased risk of malignancy, particularly non-Hodgkin lymphoma and basal cell carcinoma. The characteristics, clinical course, response to therapy and outcome of lymphomas in CHH remains unexplored. Methods: We assessed clinical features of lymphoma cases among Finnish patients with CHH. Data were collected from the Finnish Cancer Registry, hospital records, the National Medical Databases and Cause-of-Death Registry of Statistics Finland. Results: Among the 160 CHH patients, 16 (6 men, 10 women) were diagnosed with lymphoma during 1953-2016. Lymphoma was diagnosed in young adulthood (median age 26.4 years, range from 6.4 to 69.5 years), mostly in advanced stage. The most common lymphoma type was diffuse large cell B-cell lymphoma (DLBCL) (6/16, 38%). Eight patients received chemotherapy (8/16, 50%), and two of them survived. Standard lymphoma chemotherapy regimens were administered in the majority of cases. Altogether, eleven CHH patients died due to lymphomas (11/16, 69%). In almost all surviving lymphoma patients, the diagnosis was made either during routine follow-up or after evaluation for non-specific mild symptoms. Search for CHH-related clinical predictors demonstrated higher prevalence of recurrent respiratory infections, in particular otitis media, and Hirschsprung disease in patients with lymphoma. However, three patients had no clinical signs of immunodeficiency prior to lymphoma diagnosis. Conclusion: DLBCL is the most common type of lymphoma in CHH. The outcome is poor probably due to advanced stage of lymphoma at the time of diagnosis. Other CHH-related manifestations poorly predicted lymphoma development, implying that all CHH patients should be regularly screened for malignancy.
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Enfermedad de Hirschsprung , Linfoma de Células B Grandes Difuso , Osteocondrodisplasias , Enfermedades de Inmunodeficiencia Primaria , Adolescente , Adulto , Anciano , Niño , Femenino , Cabello/anomalías , Enfermedad de Hirschsprung/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Osteocondrodisplasias/congénito , Osteocondrodisplasias/epidemiología , Adulto JovenRESUMEN
Importance: Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far. Objective: To elucidate the genetic spectrum of UHS. Design, Setting, and Participants: This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021. Main Outcomes and Measures: Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes. Results: The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene. Conclusions and Relevance: This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.
Asunto(s)
Enfermedades del Cabello , Femenino , Masculino , Humanos , Estudios de Cohortes , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/genética , Secuenciación del Exoma , Cabello/anomalías , TransglutaminasasRESUMEN
Cartilage-hair hypoplasia (CHH) is a syndromic immunodeficiency characterized by metaphyseal dysplasia, cancer predisposition, and varying degrees of anemia. It may present as severe combined immunodeficiency in infancy, or slowly progress until fully manifesting in late adolescence/adulthood. No targeted treatment is currently available, and patients are usually managed with supportive measures, or are offered a bone marrow transplant if the clinical phenotype is severe and a suitable donor is available. We report the case of a young girl presenting with transfusion-dependent erythropoietic failure and immunological features resembling autoimmune lymphoproliferative syndrome who responded well to empirical sirolimus. She later developed a marked growth delay, which was ultimately attributed to metaphyseal dysplasia. A diagnosis of CHH was reached through whole-genome sequencing (WGS), after a less sensitive genetic diagnostic strategy failed. The patient eventually underwent a haploidentical bone marrow transplant due to progressive combined immunodeficiency manifested as cryptococcal meningoencephalitis. This case illustrates the potential role of sirolimus in correcting anemia and partially controlling the immune aberrations associated with CHH, and serves as a reminder of the invaluable role of WGS in diagnosing patients with complex and atypical presentations.
Asunto(s)
Anemia , Eritropoyesis , Adulto , Femenino , Cabello/anomalías , Enfermedad de Hirschsprung , Humanos , Osteocondrodisplasias/congénito , Enfermedades de Inmunodeficiencia Primaria , Sirolimus/uso terapéuticoRESUMEN
Uncombable hair syndrome presents with frizzy hair in early childhood. Isolated hair manifestations are usually observed; however, systemic involvement of the nervous system, eyes, and ears have also been reported. The syndrome has been classified into three subtypes, correlating with the three mutated genes: peptidyl arginine deiminase, type III; transglutaminase 3; and trichohyalin. This article presents the clinical picture of uncombable hair syndrome with special attention to its systemic manifestations. It also addresses its molecular aspects. Google Scholar was used to retrieve relevant publications. Clinical and molecular data were tabulated and frequencies were calculated. At least 127 cases were identified. Congenital hair defects were reported in two-thirds of cases, in which hair texture (83%), color (52%), density (15%), and growth (11%) were impaired. Uncombable hair rarely involves the eyebrows and eyelashes, and it may co-occur with loose anagen hair syndrome, androgenic alopecia, alopecia areata, and scarring alopecia. Pathologies of the skin, nails, and teeth were reported among 63%, 28%, and 25%, respectively. Systemic abnormalities were not uncommon. Dysmorphic features (n = 8), and neuropsychiatric/developmental (n = 8), ophthalmic (n = 7), otic (n = 4), and cardiopulmonary (n = 3) manifestations were also reported. Molecular genetic analysis of all patients is recommended to identify genotype-phenotype correlation. A general pediatric review might be needed to rule out any potential systemic association.