Hypophosphatasia (HPP) is a rare genetic disorder characterized by impaired mineralization (“calcification”) of bones and teeth. The common mode of inheritance is autosomal recessive. Radiographically, it resembles rickets and is defined by low serum alkaline phosphatase activity. It is an inborn error of metabolism in which the activity of tissue non-specific (liver/bone/kidney) alkaline phosphatase is deficient, while the activity of intestinal and placental enzymes remains normal.

HPP occurs due to a genetic mutation in the ALPL gene, which leads to deficient activity of alkaline phosphatase, resulting in substrate accumulation, such as inorganic pyrophosphate. This disrupts bone mineralization and impairs calcium and phosphate regulation, leading to progressive damage to multiple vital organs. The resulting issues include bone destruction and deformity, profound muscle weakness, seizures, impaired renal function, respiratory failure, and widespread inflammation of bones [5].

The disease’s clinical manifestations vary greatly; they can range from stillbirth devoid of mineralized bone to a mild form with late adult onset, manifesting as musculoskeletal pain, arthropathy, fractures in the lower extremities, early tooth loss, or an incidental discovery of decreased serum ALP activity [6]. There are six major types of hypophosphatasia, with neonatal hypophosphatasia being the most severe form [7]. It can present at birth or be diagnosed in utero by radiographic examination of the fetus. It primarily results in skeletal and neurological problems, such as seizures. Skeletal issues include marked shortening of long bones, underdeveloped ribs, and chest deformity with a “moth-eaten” appearance at the ends of long bones, and severe deficiency of ossification throughout the skeleton, as seen in our patient. Some pregnancies may result in stillbirth, while some newborns can survive for several days [4]. If left untreated, neonates can die of respiratory failure due to chest deformities and weakness.

Hypophosphatasia can be diagnosed clinically in patients with features such as rickets-like bone changes, bone demineralization, fragility fractures, reduced muscular strength, chest deformity, pulmonary hypoplasia, nephrolithiasis, nephrocalcinosis, and chondrocalcinosis [8]. The supporting lab investigation including decreased blood unfractionated alkaline phosphatase activity, with or without the detection of biallelic loss of function variants or a heterozygous ALPL variant with a dominant-negative effect using molecular genetic testing [9]. The best initial test is measuring low levels of alkaline phosphatase activity for the patient’s age, with an exception in pseudohypophosphatasia where levels are extremely rare and normal. Calcium and phosphorus levels are typically normal or elevated.Measurement of PLP levels could have added diagnostic value as it is typically elevated in hypophosphatasia due to defective metabolism. Unfortunately, PLP testing was not available at our institution at the time, which we acknowledge as a limitation. Elevated phosphoethanolamine levels in blood or urine can also support the diagnosis. Diagnostic radiographic changes for hypophosphatasia can further aid in diagnosis. Although molecular genetic testing can confirm the diagnosis, it is expensive and often unnecessary for diagnosis.

Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase, or asfotase alfa (Strensiq), was approved by the FDA in 2015 and is used as first-line therapy in infants, children, and some adults with HPP. Asfotase alfa improves pulmonary function, muscular strength, bone mineralization, and survival in patients with life-threatening HPP. However, discontinuing asfotase alfa leads to the return of bone hypo mineralization [10]. Infusion of plasma rich in ALP activity can also be used. Bone marrow transplantation using donors with normal TNSALP values has been successful [11]. Supportive therapies include genetic counseling, vitamin B6 for patients with seizures, surgery to relieve raised intracranial pressure or repair fractures, pain management by NSAIDs, dental care to preserve primary dentition, dietary calcium restriction, hydration, certain diuretics, possibly calcitonin injections, physical therapy, and psychosocial support. Misdiagnosis can lead to problems, as high doses of vitamin D, calcium supplements, and bisphosphonates can worsen symptoms.

The clinical course of HPP often improves spontaneously as the child matures. Early death can occur, with mortality rates nearly 100% in perinatal cases and 50% in infantile cases [12]. Severe progressive complications can cause lifelong morbidities. According to the literature, patients with neonatal hypophosphatasia who received enzyme replacement therapy had good survival rates [13]. The strength of this case report includes that it is one of the rare entities that is not much published and the diagnosis of neonatal hypophosphatasia requires clinical and laboratory work-up. Neonatal hypophosphatasia should be suspected in infants with prenatal skeletal abnormalities, respiratory distress due to chest wall deformities, or early-onset seizures—particularly pyridoxine-responsive seizures. Key diagnostic clues include poor skeletal mineralization on X-ray, low serum alkaline phosphatase (ALP) levels for age, and elevated substrates such as pyridoxal 5′-phosphate (PLP) and phosphoethanolamine (PEA). Confirmation is achieved through genetic testing for mutations in the ALPL gene. Early recognition is crucial for timely initiation of enzyme replacement therapy. As our patient had not received enzyme replacement therapy, its effects on survival rate are not investigated. Confirmation from genetic testing may not be required to start enzyme replacement therapy if other clinical, radiographic, and laboratory findings strongly suggest HPP.