Arcanjo Adriano Miguel, de Souza Amanda Fernandes, de Souza Quedas Elisangela Pereira, de Menezes Correia-Deur Joya Emilie, Ferreira Dalton Libanio, de Almeida Toledo Sergio Pereira, Lourenço Delmar Muniz
Endocrine Genetics Unit, Laboratory of Cellular and Molecular Endocrinology (LIM-25), Division of Endocrinology and Metabolism, Hospital das Clínicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), São Paulo, São Paulo SP, 01246-903, Brazil.
Department of Radiology, Hospital das Clínicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), São Paulo, São Paulo, Brazil.
JBMR Plus. 2025 Mar 2;9(4):ziaf026. doi: 10.1093/jbmrpl/ziaf026. eCollection 2025 Apr.
Primary hypertrophic osteoarthropathy (PHO) is a rare autosomal recessive disease caused by pathogenic variants (PVs) in and genes whose phenotypes are, respectively, designated as PHOAR1 and PHOAR2. Recently, a dominant inherited form (PHOAD) was identified in heterozygotes whose PHO penetrance is widely unknown, and data on phenotype are markedly limited. Our aim was to reveal the penetrance and extend/refine data on phenotype of heterozygotes. Both genes were sequenced using Sanger sequencing. The 4 probands had a typical complete form (CF) of PHO. Mean ages at symptom onset and clinical diagnosis were, respectively, 18.5 ± 2.7 (16-22) years and 22 ± 3.4 (18-26) years. They were homozygotes for (p.Q188R, p.C420F, p.A176T; p.G104) PVs; 2 were novel variants. We focused on 14 heterozygous screened relatives from 3 families: 5 elderly individuals (mean age: 78 ± 6.7 [72-86] years) of the parental generation were affected, 2 by incomplete form (IF) and 3 with isolated digital clubbing (IDC). Combining our 14 carriers and 33 reported so far, the estimated overall PHO penetrance was 70%, being significantly higher in men (83% vs 50%; .024) and individuals carrying truncated PVs (88% vs 53%; .053). In turn, the periostosis penetrance rate in women was 28% (5/18), including our oldest patient (86 years). In the probands, the predominant phenotypes were CF (64%) and IF (36%). Among screened carriers, phenotypes were IDC (41%) followed by IF and fruste form (FF) (28%, each), whereas IDC and FF were the predominant phenotypes in screened men and women, respectively. As a novelty, we uncovered an incomplete penetrance of PHO in heterozygotes, with higher rates in elderly individuals, males, and those with truncated PVs. Regarding phenotype, PHO is more pronounced in males, periostosis is likely more frequent in females than previously documented in PHOAR2, and IDC may represent a distinct clinical feature in heterozygotes.
原发性肥厚性骨关节病（PHO）是一种罕见的常染色体隐性疾病，由 和 基因的致病变异（PVs）引起，其表型分别被命名为PHOAR1和PHOAR2。最近，在 杂合子中发现了一种显性遗传形式（PHOAD），其PHO外显率广泛未知，且关于表型的数据明显有限。我们的目的是揭示 杂合子的外显率，并扩展/完善其表型数据。使用桑格测序法对这两个基因进行测序。4名先证者患有典型的完全型（CF）PHO。症状出现和临床诊断时的平均年龄分别为18.5±2.7（16 - 22）岁和22±3.4（18 - 26）岁。他们是 （p.Q188R、p.C420F、p.A176T；p.G104）PVs的纯合子；2个是新变体。我们重点关注了来自3个家庭的14名经筛查为 杂合子的亲属：亲代的5名老年个体（平均年龄：78±6.7 [72 - 86]岁）受影响，2人表现为不完全型（IF），3人有孤立性杵状指（IDC）。将我们的14名携带者与迄今报道的33名相结合，估计PHO的总体外显率为70%，男性（83%对50%；P = 0.024）和携带截短型 PVs的个体（88%对53%；P = 0.053）的外显率显著更高。反过来，女性的骨膜增生外显率为28%（5/18），包括我们年龄最大的患者（86岁）。在先证者中，主要表型为CF（64%）和IF（36%）。在经筛查的携带者中，表型为IDC（41%），其次是IF和顿挫型（FF）（各28%），而IDC和FF分别是经筛查男性和女性的主要表型。作为一项新发现，我们发现 杂合子中PHO存在不完全外显，在老年个体、男性以及携带截短型PVs的个体中发生率更高。关于表型，PHO在男性中更明显，骨膜增生在女性中可能比PHOAR2中先前记录的更常见，并且IDC可能是 杂合子的一种独特临床特征。
