A Wide Spectrum of Autoimmune Manifestations and Other Symptoms Suggesting Immune Dysregulation in Patients With Cartilage-Hair Hypoplasia

Abstract

Background: Mutations in RMRP, encoding a non-coding RNA molecule, underlie cartilage-hair hypoplasia (CHH), a syndromic immunodeficiency with multiple pathogenetic mechanisms and variable phenotype. Allergy and asthma have been reported in the CHH population and some patients suffer from autoimmune (AI) diseases.Objective: We explored AI and allergic manifestations in a large cohort of Finnish patients with CHH and correlated clinical features with laboratory parameters and autoantibodies.Methods: We collected clinical and laboratory data from patient interviews and hospital records. Serum samples were tested for a range of autoantibodies including celiac, anti-cytokine, and anti-21-hydroxylase antibodies. Nasal cytology samples were analyzed with microscopy.Results: The study cohort included 104 patients with genetically confirmed CHH; their median age was 39.2 years (range 0.6–73.6). Clinical autoimmunity was common (11/104, 10.6%) and included conditions previously undescribed in subjects with CHH (narcolepsy, psoriasis, idiopathic thrombocytopenic purpura, and multifocal motor axonal neuropathy). Patients with autoimmunity more often had recurrent pneumonia, sepsis, high immunoglobulin (Ig) E and/or undetectable IgA levels. The mortality rates were higher in subjects with AI diseases (χ(2)2 = 14.056, p = 0.0002). Several patients demonstrated serum autoantibody positivity without compatible symptoms. We confirmed the high prevalence of asthma (23%) and allergic rhinoconjunctivitis (39%). Gastrointestinal complaints, mostly persistent diarrhea, were also frequently reported (32/104, 31%). Despite the history of allergic rhinitis, no eosinophils were observed in nasal cytology in five tested patients.Conclusions: AI diseases are common in Finnish patients with CHH and are associated with higher mortality, recurrent pneumonia, sepsis, high IgE and/or undetectable IgA levels. Serum positivity for some autoantibodies was not associated with clinical autoimmunity. The high prevalence of persistent diarrhea, asthma, and symptoms of inflammation of nasal mucosa may indicate common pathways of immune dysregulation.

RNA polymerase III transcription as a disease factor

“…Compound heterozygous or homozygous mutations in the RMRP gene have been found in three types of related diseases, anauxetic dysplasia (AD), cartilage hair hypoplasia (CHH), and metaphyseal dysplasia without hypotrichosis (MDWH), which are collectively referred to as cartilage hair hypoplasia-anauxetic dysplasia spectrum disorders (Ridanpää et al 2001;Bonafé et al 2002;Thiel et al 2005;Makitie and Vakkilainen 2012). All are characterized by short stature due to bone growth deficiency, and for the best understood CHH, sparse hair, and in many cases immunodeficiency, anemia, autoimmunity, allergy, and asthma (Vakkilainen et al 2018). The observed mutations include insertions or duplications between the TATA box and the TSS, which prevent transcription, and deletions or mutations in highly conserved region of the RNA coding region (Ridanpää et al 2001;Hermanns et al 2006).…”

A 30-Year Prospective Follow-Up Study Reveals Risk Factors for Early Death in Cartilage-Hair Hypoplasia

“…Immunodeficiency can range from asymptomatic to severe and prediction of clinical course remains a challenge. Some reports suggest Hirschsprung disease, short birth length or autoimmunity to influence disease severity (9–13). Studies exploring correlations between laboratory parameters and clinical phenotype provide contradictory results (12, 14–16).…”

How Altered Ribosome Production Can Cause or Contribute to Human Disease: The Spectrum of Ribosomopathies

“…Cartilage hair hypoplasia (CHH) is an autosomal recessive inherited disease reported first by Victor McKusick in 1965 in a population of Old Order Amish [ 89 ]. This pleiotropic disorder is characterized by short-limbed dwarfism, sparse hypoplastic hair, defective T-cell immunity, hypoplastic anemia, increased risk of developing malignancies [ 90 , 91 ], and other symptoms [ 92 , 93 , 94 , 95 ]. Many of these symptoms, including immunodeficiency and cancer predisposition, are considered responsible for a shorter life expectancy in these patients [ 96 ].…”