Neonatal hypophosphatasia: a case report of a rare genetic disorder

Abstract

Background

Neonatal Hypophosphatasia is a rare condition attributed to loss of function mutations in the ALPL gene, resulting in diminished activity of Tissue Non-Specific Alkaline Phosphatase (TNSALP). While it can manifest at various life stages, neonatal onset is particularly ominous, often leading to fatal outcomes. The syndrome’s diverse clinical manifestations pose a diagnostic challenge, necessitating a meticulous approach to rule out other differentials.

Case presentation

In our case, the observation of neonate’s anomalous posture prompted a comprehensive diagnostic evaluation, including imaging studies. The results of the babygram raised concerns about a potential metabolic bone disorder, leading to a thorough investigation of alkaline phosphate levels. Persistent low levels further raised suspicion for Hypophosphatasia. We provided supportive treatment to the patient which included ventilator support, anti-epileptics for seizures, initially fluids later feed optimization with low calcium formula, vitamin D restriction, and gentle handling along with antibiotics for existing infection. Genetic testing was subsequently performed, confirming the presence of a loss of function mutation in the ALPL gene.

Conclusion

Our case highlights the significance of astute clinical observation, imaging studies, and biochemical assessments in unveiling this rare disorder. Early identification through a systematic approach allows for timely initiation of treatment, potentially ameliorating outcomes. By elucidating the disease’s symptoms, this case contributes to a better understanding of its natural history, emphasizing the imperative for early intervention to enhance patient prognosis.

Background

We describe a rare case of Hypophosphatasia, a condition that can be fatal to neonates. The ALPL gene, which codes for the tissue nonspecific alkaline phosphatase, has loss-of-function mutations that cause this extremely rare metabolic bone disease. In 1948, Dr. Campbell identified hypophosphatasia as the cause of rickets and convulsions in a newborn who also had a low level of alkaline phosphatase (ALP) [1]. More than 315 distinct mutations have been found in the gene for the Tissue-nonspecific isozyme of alkaline phosphatase (TNSALP) [2]. TNSALP breaks down pyrophosphate phosphodiesterase to produce inorganic phosphate, which aids in the production of hydroxyapatite. Pyridoxine’s phosphorylated form is hydrolyzed by TNSALP in the brain, enabling this vitamin to pass through the blood-brain barrier [3].

In our case, a neonate’s aberrant posture initially raised questions, and later, several clinical findings let us determine that the infant had Hypophosphatasia. Our goal is to shed light on the disease’s symptoms so that we may better understand its natural history and start treating patients earlier, improving the outcomes.

Case presentation

We report a case of a 10-day-old male neonate born to a Gravida 3 Para 1 + 1 mother at 39 weeks of gestation via emergency lower segment C- section with APGAR scores of 8 at 1 min and 9 at 5 min. The antenatal scans were normal, and mother had no known co-morbids. The patient was referred from secondary care hospital on the 2nd day of life. On newborn assessment, there was anthropometric discrepancy (Length < 3rd centile, occipito-frontal circumference (OFC) between 10th and 50th centile while the weight was just above 10th centile). Baby had issues of persistent respiratory distress soon after birth, therefore oxygen support provided via continuous positive airway pressure (CPAP), and baseline work-up (CBC, creatinine, electrolytes, CRP and PT/APTT)was done which was reported normal. Echo showed moderate persistent pulmonary hypertension of the newborn (PPHN), which resolved on repeat. On day 2 of life, the patient had a generalized tonic-clonic seizure, managed with anticonvulsants. Intra-ventricular hemorrhage, electrolyte abnormalities and hypoglycemia was ruled out. Baby was managed with Intra-Venous (IV) antibiotics and CPAP and referred to our hospital at 10th day of life. On clinical examination, the neonate exhibited a frog-leg posture with reduced spontaneous movements and hypotonia. In addition, tachypnea with sub-costal recession was noted likely due to a combination of compromised chest wall mechanics and transient PPHN.

On palpation, there was tenderness noted over the ribs and femur, suggesting possible fracture sites, while facial features were normal, and rest of the examination was unremarkable. Neonate was intubated in Emergency room and shifted to NICU for ventilator support. In our case, a multidisciplinary team approach was adopted early during the patient’s NICU admission. The team included neonatology, pediatric endocrinology, pediatric neurology, and metabolic specialists.

Ultrasound head and EEG done which was reported normal. Mild hypoxic changes were reported on MRI and MRS head. Lumbar puncture was done to rule out meningitis. Electrolytes revealed raised calcium with normal phosphate and hypomagnesemia while Parathyroid hormone (PTH), and alkaline phosphatase was low [4] and vitamin D was normal (Table 1).

Table 1.

Laboratory investigations

Date	1/6	6/6	9/6	14/6	15/6	16/6	18/6	21/6	23/6	26/6	3/7	24/7
Serum Calcium (mg/dl)					10.3			13.3	15.3	17.1	17.2	16.8
Ionized calcium (mg/dl)	5.07	6.72	4.97				5.68
Magnesium (mg/dl)	1.5		1.8
Alkaline Phosphatase (IU/L)				7	10				< 5
Phosphorus (mg/dl)		4.2	6.3		6.5
PTH (pg/ml)						3.43
1,25-OH Vitamin D (pg/ml)					80.3

Metabolic work-up showed normal CSF and plasma amino acids, lactic acid, homocysteine, ammonia and CPK, Urine for organic acid showed no significant peak. Baby-gram was done due to suspicion of metabolic bone disease which showed generalized reduced bone density and healed fractures of bilateral ribs as depicted in Fig. 1.

Fig. 1.

Babygram showing reduced mineralization especially at metaphysis and multiple healing fractures

Based on the clinical presentation and initial investigations, the differential diagnoses considered were neonatal hypophosphatasia, inborn errors of metabolism, and encephalopathy of unknown cause. A final diagnosis of neonatal hypophosphatasia was established, supported by elevated calcium levels, normal phosphate levels, markedly low alkaline phosphatase, and secondary suppression of parathyroid hormone. Although calcium was elevated, there was no renal dysfunction.

His neurological and respiratory clinical findings were also suggestive. We planned to send genetic workup to confirm our diagnosis but were unable to proceed at that time due to financial constraints. We provided supportive treatment to the patient which included ventilator support, antiepileptics for seizures, initially fluids and later feed optimization with low calcium formula, vitamin D restriction, and gentle handling along with antibiotics for existing infection.

Baby was discharged with advice of follow up with relevant lab workup to be followed as shown in Table 1. In this case, samples were preserved, and genetic testing was performed at a later stage with parental consent. This strategy allowed a definitive diagnosis even though immediate testing was not possible due to financial constraints. Genetic analysis confirmed the mutation in ALPL gene and pattern of inheritance was autosomal recessive. But unfortunately, the baby expired at 6 months of age due to progression of respiratory distress which lead to cardiopulmonary compromise, which was prior to initiation of enzyme replacement therapy due to resource limited setting.

Discussion

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.<8 > 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.

Conclusion

Hypophosphatasia, resulting from ALPL gene mutations, presents a diagnostic challenge due to its varied clinical manifestations. The neonatal onset, often fatal, necessitates a prompt and accurate diagnosis. Our case highlights the significance of astute clinical observation, imaging studies, and biochemical assessments in unveiling this rare disorder. Early identification through a systematic approach allows for timely initiation of treatment as discussed previously, potentially ameliorating outcomes. By elucidating the disease’s symptoms, this case contributes to a better understanding of its natural history, emphasizing the imperative for early intervention to enhance patient prognosis.

Patient perspective

Our child was born full term, and we did not expect this to happen, we tried our best to provide best care to our child, it was not easy to see him going through all these procedures and sometimes it is just not possible to change the outcome.

Abbreviations

HPP

Hypophosphatasia

PTH

Parathyroid hormone

CPAP

Continuous Positive Airway Pressure

ALP

Alkaline Phosphatase

TNSALP

Tissue Non-Specific Alkaline Phosphatase

Authors’ contributions

WIV: Conceptualization, Writing- Original draft preparation NC: Writing and Editing AM: Reviewing and Editing.

Funding

Not applicable.

Data availability

The dataset supporting the findings of this study is available from Aga Khan University Hospital, but it is not publicly available. It can be provided by the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Informed consent was obtained from the parent’s legal guardian for publication of this case report. A copy of consent is available for review by the Editor-in-chief of this journal.

Competing interests

The authors declare no competing interests.