Challenges in Hypophosphatasia: Suspicion, Diagnosis, Genetics, Management, and Follow-Up.

BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (ALP) activity. This results in a distinctive biochemical profile marked by low serum ALP levels and elevated pyridoxal-5-phosphate (PLP). The clinical spectrum of HPP ranges from perinatal lethality to asymptomatic cases, presenting significant diagnostic and therapeutic challenges. SUMMARY: Diagnosis of HPP relies on identifying the characteristic biochemical signature (low ALP, high PLP), concomitant with skeletal (osteomalacia, rickets, pseudofracture) or extraskeletal (muscle weakness, musculoskeletal pain, dental) manifestations. Current diagnostic frameworks lack uniformity, highlighting the imperative for a standardized diagnostic approach. Molecular genetic testing plays a pivotal role in making the diagnosis of HPP, but difficulties persist in diagnosing milder cases and correlating genotypes with phenotypes. Comprehensive multidisciplinary care is indispensable, with enzyme replacement therapy (ERT) proving efficacious in severe cases and more nuanced management approaches for milder presentations. Overcoming challenges in ERT initiation, treatment response assessment, dose titrations, and long-term surveillance necessitates further refinement of management guidelines. KEY MESSAGE: Mild forms of HPP and asymptomatic carriers of pathogenic ALPL variants pose substantial diagnosis and management challenges. Developing consensus-driven guidelines is crucial to enhance clinical outcomes and patient care.

Spontaneous reshaping of vertebral fractures in an adolescent with osteogenesis imperfecta.

Background: Vertebral compression fractures (VFs) are a common and severe finding in patients with osteoporosis. In children, VFs have the unique potential to reshape and regain their original configuration. Spontaneous vertebral body reshaping (i.e., medication-unassisted) has been reported in secondary osteoporosis. Here we describe a previously unreported spontaneous vertebral reshaping in an adolescent with osteogenesis imperfecta (OI) with multiple vertebral fractures. Case report: A 17-year-old female was diagnosed with OI type I at 5 years of age caused by a novel frameshift variant in COL1A1 (NM_000088.4: c.540delC; p.Met181TrpfsTer84). Due to parental reservations about medication, she had never received bisphosphonate or any other bone active therapy. A lateral spine X-ray demonstrated transparent bones and no VF. However, previous spine X-rays taken at age of 6 years at an external institution showed VFs in T5-7 (Genant semiquantitative method grade I-II). The two lateral spine x-rays, taken 11 years apart, demonstrate that substantial spontaneous vertebral reshaping occurred without bone active therapy during puberty. Discussion: Vertebral reshaping is explained by the stabilization of bone mineral density (BMD) and the remaining growth capacity the children. We hypothesize that spontaneous reshaping may occur in milder forms of OI, and that puberty may be a key mediator of the phenomenon. In all children with OI and vertebral fractures, we nevertheless recommend bisphosphonate therapy since it improves bone mass, BMD, vertebral shape, physical activity and reduces fracture rates.

The landscape of retesting in childhood-onset idiopathic growth hormone deficiency and its reversibility: a systematic review and meta-analysis.

Objective: Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result of 'GHD reversal'. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD aetiology, GH cut-off and retesting time point, with heterogeneous results. We aimed to systematically analyse the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points. Methods: PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating the reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models. Results: Of the 29 studies initially identified, 25 provided sufficient detail for IGHD analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (P = 0.0013). Pooled (95% CI) reversal rates were 80% (59-92%, n = 227), 73% (62-81%, n = 516) and 55% (41-68%, n = 1287) for cohorts using retesting GH cut-offs of 3-4 ng/mL, 5-6 ng/mL and 7.7-10 ng/mL, respectively. Individuals retested at FH (n = 674) showed a pooled reversal rate of 74% (64-82%) compared to 48% (25-71%) when retested before FH (n = 653). Conclusion: Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.