罕见疾病是一个经常被忽视的公共卫生问题。虽然很少见,平均每百万人口100-500人,由于这些疾病的复杂表现和需要专业护理,这些疾病在儿科牙科领域是一个重大挑战。诸如X连锁的低磷酸盐血症病(XLH),低磷酸盐血症(HPP),成骨不全症(OI)体现了全身健康问题和口腔健康的交集,需要多学科的方法来进行有效的管理。牙医经常在通过牙齿表现识别遗传改变,然后将患者转介给遗传学家以进行明确诊断方面发挥关键作用。X连锁低磷血症是最常见的遗传病,患病率为1/20,000-1/60,000。XLH的特点是生长迟缓,身材矮小,与运动技能降低相关的下肢鞠躬,骨关节疼痛,低张力,牙齿和牙周异常.XLH是由于PHEX基因中的失活突变引起成纤维细胞生长因子23(FGF23)的过量产生。FGF23浓度的增加代表了XLH的主要致病机制,刺激尿磷酸盐丢失和肾24-羟化酶活性,并降低肾脏1α-羟化酶活性,同时产生1,25-二羟基维生素D(1,25(OH)2D)。PHEX蛋白也在成骨细胞中表达,骨细胞,和成牙本质细胞.无论FGF23对磷酸盐稳态的全身作用如何,成牙本质细胞分化,和牙本质的形成,其过度表达直接减少成骨细胞分化和基质矿化。在XLH患者中,FGF23引起的1,25(OH)2D的缺乏导致牙釉质矿化不良,牙齿表面存在裂纹。XLH患者复发性牙脓肿伴瘘管。射线照相研究强调了纸浆室的普遍扩大,有短根的磨牙,和牛磺酸的外表。低磷酸盐症(HPP)是牙齿表现先于全身症状的另一种情况;它是一种罕见的遗传性疾病(严重形式的1/300,000,中等形式的1/100,000。由于漏诊了中度疾病,发病率可能被低估了)。它主要影响骨骼和牙齿矿化。它是由位于1号染色体短臂上的ALPL基因中的致病性变异突变引起的,并编码非组织特异性碱性磷酸酶(TNSALP)酶。TNSALP缺乏导致维生素B6(吡哆醇)缺乏和碱性磷酸酶底物的病理积累,这可能是骨外表现的原因。如神经系统的(吡哆醇敏感型癫痫)以及肌肉和关节的受累(关节病,肌肉疲劳/张力减退)。2至4岁(有时更早)的早期非创伤性乳牙缺失,未吸收的根是疾病的征兆。牙齿活动先于牙齿/牙齿脱落,通常没有相关的牙龈炎症或疼痛。主切牙是受影响最大的牙齿,失去的乳牙的数量和类型与疾病的严重程度成正比。从放射学的角度来看,特征性体征包括局部或全身水平牙槽骨丢失,大型纸浆室,球内钙化,和减少釉质厚度。成骨不全症,或者脆性骨病,是一种罕见的疾病,以骨脆性和骨质减少为特征。它结合了不同严重程度的骨骼体征(主要是骨折,过度松弛,和韧带畸形)和额外的骨骼体征(蓝色巩膜,耳聋,血管脆性)。它也可能涉及牙本质发育不全。临床表现的严重程度是高度可变的,从可能被忽视的中度形式到在围产期致命的主要形式。成骨不全症的出生患病率约为10,000人中的1人。在大约90%的案例中,由于COL1A1,COL1A2或IFITM5基因的单等位基因突变,是一种常染色体显性疾病.百分之十的病例是以牙本质发育不全为特征的隐性形式,其中牙齿表现包括牙齿变色和虚弱。及时识别这些罕见遗传疾病的牙齿表现,可以使提供者甚至在出现系统性并发症之前就做出早期诊断,因此,儿科牙医在识别和管理这些患者方面发挥着关键作用。一旦怀疑诊断,牙医应转介患者进行基因评估,以确保与儿科医生合作进行多学科管理和开始医学治疗,内分泌学家和其他健康专家。牙科专业人员的作用不仅限于这些罕见疾病的诊断,但它也包括提供特定的,为患者量身定制的治疗方法,鼓励定期牙科护理和教育患者的最终目标,不仅促进口腔健康,而且促进患者的整体福祉。
Rare diseases are an often an overlooked public health problem. Although they are infrequent, occurring on average in 100-500 people per million, these diseases represent a significant challenge in paediatric dentistry due to their complex manifestations and the need for specialised care. Conditions such as X-linked hypophosphatemic rickets (XLH),
hypophosphatasia (HPP), and osteogenesis imperfecta (OI) exemplify the intersection of systemic health issues and oral health, requiring a multidisciplinary approach for their effective management. Dentists frequently play a crucial role in identifying genetic alterations through their dental manifestations and then referring patients to the geneticist for a definitive diagnosis. X-linked hypophosphatemia is the most common genetic form of rickets, with a prevalence of 1/20,000 - 1/60,000. XLH is characterised by stunted growth with disproportionate short stature, bowing of the lower limbs associated with reduced motor skills, osteoarticular pain, hypotonia, and dental and periodontal anomalies. XLH is due to inactivating mutations in the PHEX gene which cause excessive production of fibroblast growth factor 23 (FGF23). Increased concentration of FGF23 represents the main pathogenetic mechanism of XLH, stimulating urinary phosphate loss and renal 24-hydroxylase activity, and reducing renal 1α-hydroxylase activity with insufficient production of 1,25 -dihydroxy-vitamin D (1,25(OH)2D). PHEX protein is also expressed in osteoblasts, osteocytes, and odontoblasts. Regardless of FGF23\'s systemic effects on phosphate homeostasis, odontoblast differentiation, and dentin formation, its overexpression directly reduces osteoblast differentiation and matrix mineralisation. In patients with XLH, the deficit of 1,25(OH)2D induced by FGF23 causes poor enamel mineralisation with presence of cracks on teeth surface. XLH patients have recurrent dental abscesses with fistulas. Radiographic investigations highlight a generalised enlargement of the pulp chambers, molars with short roots, and a taurodontic appearance.
Hypophosphatasia (HPP) is another condition in which dental manifestations precede systemic symptoms; it is a rare genetic disease (1/300,000 for severe forms, 1/100,000 for moderate forms. The incidence is perhaps underestimated due to missed diagnosis of moderate forms of the disease). It mainly affects bone and dental mineralisation. It is caused by pathogenic variant mutations in the ALPL gene which is located on the short arm of chromosome 1 and encodes the non-tissue-specific alkaline phosphatase (TNSALP) enzyme. TNSALP deficiency results in vitamin B6 (pyridoxine) deficiency and pathological accumulation of alkaline phosphatase substrates which may be responsible for extra-osseous manifestations, such as neurologic ones (pyridoxine sensitive seizures) as well as involvement of muscles and joints (arthropathies, muscle fatigue/hypotonia). Early non-traumatic loss of primary teeth between the ages of 2 and 4 years (and sometimes earlier) with an intact, non-resorbed root is a sign of disease. Tooth mobility precedes exfoliation of the tooth/teeth, most often without associated gum inflammation or pain. The primary incisors are the most affected teeth, and the number and type of primary teeth lost are proportional to the severity of the disease. From a radiologic perspective, characteristic signs include localised or generalised horizontal alveolar bone loss, large pulp chambers, intrapulpal calcifications, and reduced enamel thickness. Osteogenesis imperfecta, or brittle bone disease, is a rare condition characterised by bone fragility and osteopenia. It combines skeletal signs of varying severity (mainly fractures, hyperlaxity, and ligament deformities) and extra skeletal signs (bluish sclera, deafness, vascular fragility). It may also involve dentinogenesis imperfecta. The severity of clinical manifestations is highly variable, ranging from moderate forms that can go unnoticed to major forms that are lethal in the perinatal period. The birth prevalence of osteogenesis imperfecta is approximately 1 in 10,000 people. In approximately 90% of cases, it is an autosomal dominant disease due to monoallelic mutations in the COL1A1, COL1A2 or IFITM5 genes. Ten percent of cases are recessive forms characterised by dentinogenesis imperfecta, where the dental manifestations include teeth discoloration and weakness. The timely recognition of dental manifestations of these rare genetic diseases can allow providers to make an early diagnosis even prior to the development of systemic complications, and for this reason paediatric dentists have a key role in the recognition and management of these patients. Once the diagnosis is suspected, the dentist should refer patients for a genetic evaluation so as to ensure multidisciplinary management and initiation of medical therapies with the collaboration of paediatricians, endocrinologists and other health specialists. The role of dental professionals is not limited to the diagnosis of these rare diseases, but it also encompasses delivering specific, patient-tailored treatments, encouraging preventive care with regular dental visits and educating patients with the ultimate goal to promote not only oral health but the patient\'s overall wellbeing.