Department of Endocrinology, Seth G.S Medical College & KEM Hospital, OPD, Parel, Mumbai, Maharashtra, 400012, India.
Department of Endocrinology, Brown University, 375 Wampanoag Trail, Providence, RI, 02913, USA.
Calcif Tissue Int. 2024 Feb;114(2):137-146. doi: 10.1007/s00223-023-01156-2. Epub 2023 Nov 19.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.
遗传性低血磷性佝偻病伴高钙尿症（HHRH）是一种罕见的磷稳态失调疾病。我们描述了一个经基因证实的 HHRH 家系的单中心经验，并对报道的双等位基因突变的先证者及其单等位基因突变的亲属进行了系统的表型-基因型相关性分析。详细的临床、生化、放射学和遗传数据从我们的中心检索，并对 Pub-Med 和 Embase 数据库进行了系统的综述，以确定基因证实的患者和亲属。我们中心的 9 名受试者（先证者：5 名）携带双等位基因 SLC34A3 突变（新发现：2 名），从佝偻病/骨软化症到正常骨密度不等，所有患者均存在低磷血症和高钙尿症。我们描述了首例基因证实的 HHRH 伴有腱病的病例。另一名低磷血症、缺铁性贫血和非肝硬化门脉周围纤维化的患者，其 FGF23 升高，最初误诊为肿瘤性骨软化症。对 58 名先证者（携带双等位基因 SLC34A3 突变；35 名男性）进行系统回顾发现，70%的患者有早发性 HHRH 和肾钙化，10%的患者有晚发性 HHRH。无骨骼受累的先证者中，c.575C>T p.（Ser192Leu）变异发生在 53%。在 110 名携带单等位基因 SLC34A3 突变的亲属中，中位年龄 38 岁，观察到肾钙化、低磷血症、高 1,25（OH）D 和高钙尿症分别为 30%、22.3%、40%和 38.8%。肾钙化与年龄相关，但在截断和非截断变异体中相似。虽然大多数亲属无症状骨骼受累，但 6/12（50%）的骨密度较低。我们描述了印度首例单中心 HHRH 病例系列，具有不同的表型。在系统综述中，亲属中频繁的肾钙化和低骨密度（HHRH 特征）与单等位基因突变相关，值得关注。
