Introduction:
During the period from 24 weeks of gestation until birth, approximately 80 % of the fetus's bone mineral content is formed. Neonatal bone disorders refer to a range of conditions affecting bone development, either due to structural abnormalities or problems with mineralization, which begin in the fetus. Advanced fetal ultrasound technology can provide clear images of the bones, enabling the detection of any abnormalities starting in the second trimester. In some cases, further molecular testing may be necessary to confirm the diagnosis before or after birth. Timely identification and proper management of these disorders are crucial for promoting healthy bone development throughout childhood, adolescence, and adulthood.
What Are the Congenital Bone Defects in Children?
1. Structural Bone Defects:
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Osteogenesis Imperfecta: Osteogenesis Imperfecta (OI) is a genetic disorder characterized by increased bone fragility and low bone mass. It affects both genders and ethnic groups, with an incidence of approximately one in 10 to 20,000 births. Most cases (around 90 %) are caused by defects in the genes COL1A1 and COL1A2, resulting in abnormalities in Type 1 collagen, the primary component of bone. There are different types of OI, ranging from mild to severe forms. The traditional classification includes Type I (mildest), Type III (severe with multiple fractures and limb deformities), Type IV (moderate severity), and Type II (perinatal lethal). However, new classifications have been proposed.
The healthcare professional may detect OI in severe forms during routine antenatal ultrasound scans, showing skeletal abnormalities such as bowed limbs, fractures, and small chest size. Infants with severe OI may develop respiratory insufficiency shortly after birth, requiring respiratory support. In other cases, severely affected babies may present with short stature, bowed limbs, and multiple fractures at birth. Mild and moderate forms of OI may occur with features like a short bowed femur or dislocated hip. A skeletal survey, imaging, and genetic testing are vital for diagnosis confirmation.
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Other Skeletal Dysplasias: Skeletal dysplasias refer to a group of heritable disorders that affect the development of the fetal skeleton during pregnancy. One common feature is the congenital bowing of long bones, especially the femurs, which can be detected in the second-trimester ultrasound. Compared to normative data, the length of long bones helps determine whether there is primary rhizomelic (proximal) or mesomelic (middle) shortening. In the neonatal period, some of the notable skeletal dysplasias include Campomelic disorders, Thanatophoric dysplasias, Osteogenesis Imperfecta (OI), short rib dysplasia, hypophosphatasia, Type 2 collagen disorders, Stuve Weidman dysplasia, and achondroplasia, among others. These conditions can be identified on antenatal ultrasound scans, and some of them are lethal in the neonatal period due to small chest circumference and associated pulmonary hypoplasia.
Variations in the FGFR3 gene can give rise to a range of chondrodysplasias, including severe thanatophoric dysplasia and milder hypochondroplasia.FGFR3 is a gene found in chondrocytes (cells responsible for cartilage formation) and mature osteoblasts (cells involved in bone formation), and it plays a vital role in regulating bone growth. Achondroplasia, the most prevalent form of short-limb dwarfism, is caused by a specific mutation in the FGFR3 gene. This condition observes an autosomal dominant inheritance pattern, and most cases result from spontaneous mutations. The clinical presentation of achondroplasia includes short limbs, hands, fingers, frontal bossing, a depressed nasal bridge, and a large head observed on second-trimester antenatal ultrasound scans. The diagnosis is confirmed through molecular testing for FGFR3 mutations. At birth, the characteristic features of rhizomelic shortening of limbs, frontal bossing, midfacial hypoplasia, and macrocephaly become apparent.
2. Bone Mineralization Defects:
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Hypophosphatasia: Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder caused by a mutation in the ALPL gene, resulting in the lack of an enzyme called tissue non-specific alkaline phosphatase (TNSALP). This leads to problems with skeletal mineralization due to the accumulation of a substance called inorganic pyrophosphate. The more severe forms of HPP are inherited in an autosomal recessive pattern and occur in about one in 100,000 live births. There are different clinical presentations of HPP, and two forms relevant to the neonatal period are the Prenatal Benign and Perinatal Lethal forms. Prenatal Benign HPP is a milder form, typically detected during prenatal ultrasounds in the second trimester. It is characterized by asymmetrical skeletal changes, such as limb bowing, with or without skeletal hypomineralization. The ultrasound findings often improve in the third trimester, and after birth, the condition can range from more severe infantile HPP to a milder form affecting only the teeth (Odonto HPP).
Perinatal HPP is the most severe and life-threatening form. It is usually detected during fetal ultrasounds and presents with short, long bones, an under-mineralized skeleton, a small chest, and an abdominal circumference. At birth, affected infants have short, deformed limbs, severely hypomineralized skeletons, small chests with underdeveloped lungs, and may experience seizures due to pyridoxine deficiency. Perinatal HPP can sometimes be mistaken for hypoxic-ischemic encephalopathy, delaying diagnosis without prior suspicion. Diagnosing HPP is confirmed by low levels of serum ALP and specific radiological features, such as tongue-like lucencies in the metaphysis, rickets-like changes, and hypo-mineralized skeleton.
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Neonatal Hyperparathyroidism: Normally, the secretion of parathyroid hormone (PTH) is regulated to maintain normal levels of calcium in the bloodstream. When calcium levels drop, the parathyroid gland releases more PTH; when calcium levels are high, PTH secretion decreases. However, in neonatal severe primary hyperparathyroidism (NSHPT), there is a nearly complete loss of calcium-sensing in the parathyroid gland due to specific mutations. This leads to very high levels of serum calcium and elevated PTH, which can be life-threatening. NSHPT is a rare autosomal recessive disorder, often seen in cases of consanguinity.
Newborns diagnosed with NSHPT may initially show no signs of illness, but over time, they can develop symptoms such as difficulty thriving, feeding problems, and reduced muscle tone. One critical indicator of NSHPT is severe hypercalcemia, where calcium levels in the blood often exceed four mmol/L. X-rays reveal bone demineralization, subperiosteal resorption, rib fractures, and signs of rickets. In most cases, the hypercalcemia is severe, and the recommended course of treatment is total parathyroidectomy, a surgical procedure to remove the parathyroid glands. Bisphosphonates like pamidronate may be utilized to manage hypercalcemia before the surgery temporarily.
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Mucolipidosis Type 2 (I-Cell Disease): This rare genetic disorder follows an autosomal recessive inheritance pattern associated with mutations in the GNPTAB gene. These gene mutations impact the N-acetylglucosamine phosphotransferase complex that modifies lysosomal enzymes. An impaired transfer of calcium, mainly attributed to placental dysfunction, plays a role in the development of the metabolic bone disease observed in affected infants.
3. Various Bone Conditions with Diverse Manifestations in the Neonatal Period:
Transient neonatal hyperparathyroidism and bone disorders, similar to the conditions mentioned above, are seen in cases of maternal hypoparathyroidism. In some incidents, the birth of an affected neonate may lead to the detection of previously undiagnosed maternal disease. During the neonatal period, osteopetrosis can present with hypocalcemia, elevated PTH levels, and X-ray evidence of dense, osteosclerotic bones. Another condition known as osteopenia of prematurity can also manifest with fractures in the ribs and long bones. Babies born before 28 weeks of gestational age are particularly prone to this condition, as most of the transfer of calcium from the mother to the fetus occurs during the final trimester of pregnancy.
Conclusion:
Neonatal bone health is becoming increasingly important, not only because early management can significantly impact bone health throughout childhood, adolescence, and early adulthood. Early and accurate diagnosis is crucial for initiating life-saving treatments like enzyme replacement therapy, especially for conditions like hypophosphatasia. Research in neonatal bone disorders is rapidly advancing, with intervention studies and drug trials focusing on promoting bone health as early as the prenatal stage for conditions like osteogenesis imperfecta or during the neonatal period for achondroplasia.
