Eighteen patients participated in the study, ranging in age from 3 to 33 years, with a mean age of 13.8 (SD 8.4 years) (Table 1); five patients were under eight (27.8%), eight patients were between eight and sixteen (44.4%), and five were 18 or older (27.8%) (Table 1). Gender distribution showed seven females (38.9%) and 11 males (61.1%). Health insurance types included 8 with private coverage (44.4%) and 10 with public insurance (55.6%). Patients hailed from various Colombian regions, with Bogotá being the most represented (22.22%) (Table 1); all patients speak Spanish and none have a special ethnicity. All patients were classified with pediatric-onset hypophosphatasia based on the age of the first disease signs and symptoms.

Although in Colombia, the genetic study is not mandatory to confirm and report the disease, the 18 patients had a genetic study performed by different methodologies (Sanger sequencing, NGS and qPCR of the ALPL gene and NGS panel for skeletal dysplasias), in which at least one variant in the ALPL gene was evidenced, most of them being autosomal recessive forms (Table 2). The most frequent allele in the patients was c.892G > A p.(Glu298Lys), always associated with another variant in trans. Missense variants were the most frequent; a small duplication detected by sequencing was documented. No major rearrangements in the gene were reported. However, most heterozygous patients did not provide additional studies to rule out the presence of another variant.

Currently, c.485G > A and c.457T > A are classified as uncertain significance variants. The patient with variant c.455G > A, p.(Arg152His) in heterozygosis underwent a qPCR study, which was negative for deletions or duplications in the ALPL gene. Distribution of genotypes: 10 patients were homozygous (55.6%), six heterozygous (33.3%) and 2 compound heterozygous (11.1%).

The analysis of age at the time of the molecular study showed that seven patients were taken to molecular evaluation after ten years of age (38.9%), six patients were evaluated between 5 and 10 years of age (33.3%) and, finally, five patients underwent molecular testing between the first month of life and two years of age (27.8%). No patients were tested between 3 and 4 years of age. The median age in the molecular study was eight years (IQR between 3 and 13 years of age), ranging from 1 month to 30 years in the patients analyzed. The patients experienced this health condition for a duration spanning from 2 to 8 years (Table 2). This period was determined by calculating the time elapsed from the patient's age at the start of the molecular study to the time of the study itself. The date of the molecular study was selected as a reference point due to its objective clinical relevance for all patients. Notably, the precise date of diagnosis from the clinical history was not accessible. These data were obtained from the date of issue of the genetic result of the molecular study, information collected by the ACOPEL team.

The time elapsed between symptom onset and the time at molecular testing disclosed that, of the 18 patients, 11 (61.1%) were molecularly assessed within the first year after symptom onset, one patient was evaluated two years after symptom onset, and another at eight years, and five patients (27.8%) were assessed at least 11 years after symptom onset (Table 2).

In terms of allele frequencies, a total of 11 variants were identified. The allele distribution was as follows: c.892G > A 22%, c.659G > C 16.7%, c.382G > A 13.9%, c.571G > A 8.3%, and c.455G > A 5.6%. The alleles c.485G > A, c.457G > A, c.394G > A, c.343_348dup, and c.334G > C each appeared once (2.8%).

Concerning the specific treatment for the disease, ERT was administered to 94.4% of the patients at some stage, with 77.8% currently receiving it. The median age at treatment initiation was ten years, with varying initiation ages: 17.6% started at one year of age, 11.8% between 1.5 and 2 years, 23.5% between 5 and 10 years, and 47.1% between 11 and 30 years. Among those who received ERT, 16 out of 17 patients reported discontinuation, which occurred over a period ranging from 15 days to one year. Furthermore, 15 of 17 treated patients reported improvement upon starting the medication, especially in appetite, weight, skeletal health, gait, and pain reduction.

Ten patients completed the questionnaires (55.6%) and, in eight cases, by the parent/guardian or caregiver (44.4%).

The most affected aspects were general health, vitality, and pain, with a median score of 67.5% (IQR of 50% to 90%), 72.5% (IQR of 50% to 95%), and 73.8% (IQR of 67.5% to 100%), respectively. Likewise, the aspects that showed minor impairment in this cohort of HPP patients were role limitations due to physical health and emotional problems, with median scores of 100% in both areas. However, a minimum of 50% and 0% score was evident, respectively. Concerning physical functioning, role limitations due to physical health, and emotional problems, patients reported an acceptable health status (scores of 70% or higher). Nonetheless, a significant impairment was evident in some of the patients (Fig. 1).

Source: own elaboration in RStudio®. EW/MH: Emotional well-being/mental health; Gen-H: General health; H-Cha: Health change or transition; Phy-fun: Physical functioning; RL-EP: Role limitations due to emotional problems; RL-PF: Role limitations due to physical health, Soc-Fun: Social functioning; VIT-E/F: Vitality: Energy/fatigue

Results of the SF-36 questionnaire, according to the concept assessed.

Based on the body diagram, 61.1% of patients reported pain, with varying levels of distribution: 54.5% in 2 to 3 body areas, 27.3% in four to six, and 9.1% in 10. In total, 45 different body sites reported pain, with the lower back (26.7%) and legs (15.6%) being the most affected areas. Elbows, knees, and thorax accounted for 8.8% of reported pain.

The median scores of the maximum and minimum pain intensities experienced by patients in the past week were 3.5 and 0.5, with IQRs of 0 to 6 and 0 to 3, respectively. Furthermore, the median reported pain intensity was 3, with an IQR of 0 to 4. Current pain intensity displayed a median score of 0, with an IQR of 0 to 2, indicating that most patients experienced either no or mild pain during the study period (Fig. 2).

BPQ pain intensity results Source: own elaboration in RStudio®. Max-LastWk: Maximum in the last week; Min-LastWk: Minimum in the last week

The pain severity, measured with a median score of 2.8 (IQR: 0.3–4), peaked at 5 points. Patients commonly employed stretching, analgesics, lying down, and walking as pain-relief strategies. Conversely, standing and lifting heavy objects were identified as pain-aggravating factors.

Five patients (27.8%) reported taking analgesic medication when analyzing pain treatment, and all reported receiving acetaminophen. The perception of pain relief generated by the analgesic treatments or medicines received during the last week demonstrated that of the five patients receiving this type of medicine; three reported a 100% improvement in pain during the previous week, one reported a 50% improvement, and another 40% improvement during the same period.

During the assessment of the primary cause of pain, two patients (11.1%) attributed their pain to the effects of treatment, which encompasses medication, surgery, radiation, and prostheses, as outlined in the questionnaire. Notably, these two patients were undergoing ERT (Asfotase alfa) treatment at the time of the study. On the other hand, eleven patients (61.1%) attribute their pain to the underlying disease itself, while five patients (27.8%) perceive their pain as unrelated to the primary pathology.

The adjective used by the patients to describe the type of pain presented showed that half of the patients reported their pain to be exhausting, and the adjectives reported by 30 to 45% of the patients were fatiguing (heavy), persistent, aching/continuous, and stabbing.

Results about pain's impact on patient's lives in the past week reveal minimal interference with most activities, indicated by a median score of zero and an IQR from 0 to 3. However, mood disruption due to pain displayed more variability, with a median score of 1 and an IQR from 0 to 6 (Fig. 3).

Source: own elaboration in Microsoft Excel®

Results of the impact of pain on aspects of life during the last week.

When assessing pain interference, the median score was 1.5 (IQR: 0–3.3), with a maximum of 5.3 points. Regarding pain medication frequency, most (88.9% or 16 patients) did not take medication daily, while only two patients (11.1%) used it 1 to 2 times within 24 h.

Finally, when analyzing the need for stronger treatment or higher doses, most (83.3% and 94.4%) of patients did not feel it necessary. None of the patients reported experiencing pain medication side effects. In terms of alternative pain relief methods, 50% didn't use any, and 38.9% employed various methods, including massage (five patients), electrodes (one patient), and video games (one patient).

In respect of the perception of health, the study revealed a median response of 2.5, representing a range from excellent to fair, with an IQR spanning from 1 to 4. It is worth highlighting that all patients reported their health as good, with a noteworthy 38.9% rating as excellent.

Considering limitations in the past four weeks in activities requiring energy or involving bending, standing, or stooping due to health issues, a median response of 4 (indicating no limitation) was reported for each activity. The IQR ranged from 2 (somewhat limited) to 4 (no limitation) for these specific activities. Furthermore, more than 55% of the patients responded that they had no limitations in performing these activities in both questions.

When evaluating the limitation to perform school-type activities/work or activities with friends due to physical health problems or because of emotional or behavioral issues, a median score of 4- with no limitation was found (IQR from 3- somewhat limited to 4- with no limitation and from 4 to 4, respectively). For these two questions, 72.2% and 83.3% of patients were found to have no limitations.

For pain or bodily discomfort assessment during the last four weeks, patients had a median score of 1.5 (IQR 1 to 3; none to mild); 50% had no pain, and none reported severe or severe pain. On the perception of satisfaction in the last four weeks with relationships with friends and with their life relationship in general, patients had a median score of 1 and 1.5, respectively (IQR 1 to 2; very satisfied to somewhat satisfied). For these two questions, 66.7% and 50% of patients were found to be very satisfied, and no patients were found to be very dissatisfied.

Concerning the behavior compared to people of the same age, the patients analyzed presented a median score of 1-excellent (IQR from 1 to 3; excellent to sound). It was identified that 55.6% and 33.3% of patients answered these questions as excellent and good, respectively. No patient reported poor behavior. On aspects related to family history, five patients reported having a family member with hypophosphatasia (27.8%).

The onset of hypophosphatasia symptoms typically appeared at a median age of 2.5 years, ranging from 1 to 6 years (minimum less than one year, maximum ten years). Most patients (72.2%) experienced symptoms within the first four years of life, while the remaining 27.8% reported symptom onset between 6 and 10 years of age. All patients developed symptoms before turning 18, categorizing them as pediatric HPP cases in this study.

A median duration of six years was observed after calculating the symptoms for the patients. The IQR spanned from 4 to 14 years, indicating a range of symptom duration. The minimum reported duration was two years, while the maximum reached 30 years. Patients most frequently reported initial symptoms included respiratory distress, limb abnormalities, arm and leg pain, and walking difficulties (Fig. 4).

Source: own elaboration in RStudio®. Act-Gen: activities in general; Life-Enj: enjoy life; Rel-ship: relationships with other people; Walk-Abi: walking ability, Work-Abi: usual work

Initial symptoms reported by patients.

Patients exhibited growth and development issues, including short stature, weight challenges, and gait delays. Limb bowing was noted by one-third of patients, and roughly 28% experienced activity-limiting bone pain. Tooth problems were common, with 61.1% reporting premature tooth loss and 44.4% permanent tooth loss.

Respiratory history showed 61.1% without previous issues, but 38.9% reported dyspnea, and 16.7% had a history of pneumonia. Muscle concerns included 22.2% with muscle pain and 11.1% with muscle weakness, while most (77.8%) had no muscle-related history. 77.8% reported no renal issues for renal and other medical history, and 83.3% had no other medical history. However, 22.2% had a history of kidney stones, 5.6% had nephrocalcinosis, and 11.1% had elevated blood calcium levels. Additionally, 16.7% showed elevated blood phosphorus levels, and none reported gout history (Table 3).

Fracture incidence analysis in the patient sample revealed that three individuals (16.7%) had experienced bone fractures, all reporting their initial fracture during adolescence. One patient had two fractures (both femur), while two had three fractures each (one involving dorsal vertebra, radius, and carpal bones, and the other involving skull, tibia, and fibula). Multiple fractures resulted from trauma. Additionally, one patient experienced a pseudo fracture, which was promptly diagnosed and took about two to three months to heal.

Surgical history related to hypophosphatasia complications: 44.4% of patients had undergone surgical procedures. Among them, 22.2% mentioned osteotomies, two had kidney stone removal surgeries, one underwent tendon lengthening in both feet, and another had gum surgery for dental obstruction.

In relation to health services, 16.7% received physical therapy and nutritional consultation, while 11.1% received occupational and massage therapy. None of the patients reported receiving respiratory therapy, home health care, or acupuncture. 72.2% of patients did not receive any of the surveyed services. Only 22.2% (four patients) made changes for home modifications due to the disease, primarily in the kitchen, bedroom, and bathroom. Half of the patients did not use any surveyed aids. The most reported aids were orthoses (27.8%), ramps for people with disabilities (22.2%), and manual wheelchairs (22.2%). One patient used respiratory aids, specifically inhalers, for asthma.

In the evolution of hypophosphatasia over the last five years, 72.2% of patients report that it has improved, 22.2% report no change, and only one patient (5.6%) reports that it has worsened. On the other hand, when asked about the symptoms or complications that significantly interfere with their daily lives, ten (55.6%) mentioned pain. However, it is essential to note that the intensity of the reported pain varied among patients.