New diagnostic modalities and emerging treatments for neonatal bone disease

Abstract

Bone disease in the neonatal period has often been regarded as an issue affecting premature infants, or a collection of rare and ultra-rare disorders that most neonatologists will see only once or twice each year, or possibly each decade. The emergence of targeted therapies for some of these rare disorders means that neonatologists may be faced with diagnostic dilemmas that need a rapid solution in order to access management options that did not previously exist. The diagnostic modalities available to the neonatologist have not changed a great deal in recent years; blood tests and radiographs still form the mainstays with other techniques usually reserved for research studies, but rapid access to genomic testing is emergent. This paper provides an update around diagnosis and management of bone problems likely to present to the neonatologist.

Bone fractures in children and adolescents: a frequent problem with a diverse aetiology

“…This is because the course of the disease, possibilities of treatment (replacement therapy, symptomatic treatment) and the consequences of the evolution of the genetic disease itself and its modification by therapy all play a role in the occurrence of bone fractures. Fractures of long bones in the neonatal period indicate a severe form of disease which may lead to progressive deformations in the skeletal system and constitute a serious threat to the health and life of the newborn (5,6) . Osteogenesis imperfecta (OI; brittle bone disease) is a clinically and genetically heterogeneous increased susceptibility of bones to fractures which lead to the shortening and deformation of long bones and ribs and to impaired body proportions (ORPHA666).…”

“…This compromises the general condition of the neonate and can lead to respiratory failure (7,8) . OI aetiology mainly involves mutations in type 1 collagen genes COL1A1 and COL1A2 and in many other genes as well: BMP1, WNT1, SERPINF1, IFITM5, MBTPS2, CRTAP, LEPRE1 (5,6,8) . The diagnosis of OI is based on clinical examination, a babygram and genetic testing (Fig.…”

“…OI is a rare disease; it occurs in one in 15,000-20,000 births (8) . Osteogenesis imperfecta has been treated symptomatically for over 30 years with pharmacotherapy including mainly bisphosphonates (administered from as early as the neonatal period), and with orthopaedic treatment and rehabilitation (5)(6)(7)(8)(9) . Another cause of bone fractures occurring already in the neonatal period is hypophosphatasia (HPP), which results from a mutation in the TNSALP gene for tissue non-specific alkaline phosphatase (ORPHA436).…”

“…Bone fractures occur as early as in the perinatal period; they are accompanied by soft cranial bones, shortened and deformed long bones and bones of the chest cavity, vitamin B 6 deficiency, hypercalcaemia, and, in the most severe form of the disorder, seizures and respiratory failure. Replacement therapy is used: asfotase alfa (brand name Strensiq) is administered subcutaneously (5,10) . Bone fractures, chest abnormalities associated with rickets, radiological findings of periosteal demineralisation and elevation, and hypercalcaemia with a high level of parathormone are characteristic features of neonatal severe hyperparathyroidism (5) .…”

“…The primary causal factor of this disease is shortened pregnancy, since as much as 80% of mineral substance accumulation occurs in the third trimester. For this reason, the recommended prevention and treatment primarily involve the supplementation of phosphorus, calcium and vitamin D (4,5) .…”