Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group.

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

The challenge of hypophosphatasia diagnosis in adults: results from the HPP International Working Group Literature Surveillance.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.

Utility of genetic testing for prenatal presentations of hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited disease affecting bone and dental mineralization due to loss-of-function mutations in the ALPL gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). Prenatal benign HPP (PB HPP) is a rare form of HPP characterized by in utero skeletal manifestations that progressively improve during pregnancy but often still leave symptoms after birth. Because the prenatal context limits the diagnostic tools, the main difficulty for clinicians is to distinguish PB HPP from perinatal lethal HPP, the most severe form of HPP. We previously attempted to improve genotype phenotype correlation with the help of a new classification of variants based on functional testing. Among 46 perinatal cases detected in utero or in the neonatal period for whose ALPL variants could be classified, imaging alone was thought to clearly diagnose severe lethal HPP in 35 cases, while in 11 cases, imaging abnormalities could not distinguish between perinatal lethal and BP HPP. We show here that our classification of ALPL variants may improve the ability to distinguish between perinatal lethal and PB HPP in utero.

Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome.

Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene. This gene includes three transcripts, namely transcripts 1 and 2, encoding components of the core spliceosomal machinery (SmB' and SmB) and transcript 3 undergoing nonsense-mediated mRNA decay. All variants were located in the premature termination codon (PTC)-introducing alternative exon of transcript 3. Quantitative RT-PCR analysis revealed a significant increase in transcript 3 levels in leukocytes of CCMS individuals compared to controls. We conclude that CCMS is due to heterozygous mutations in SNRPB, enhancing inclusion of a SNRPB PTC-introducing alternative exon, and show that this developmental disease is caused by defects in the splicing machinery. Our finding confirms the report of SNRPB mutations in CCMS patients by Lynch et al. (2014) and further extends the clinical and molecular observations.