Short report Aled Picton ‍ ‍,1 Ruchi Nadar,2 Alexandra Pelivan,1 Vidya Garikapati ‍ ‍,1 Vrinda Saraff ‍ ‍2 1 Neonatal Unit, Birmingham Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 2 Department of Paediatric Endocrinology and Diabetes, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom Correspondence to Dr Vrinda Saraff, Department of Paediatric Endocrinology and Diabetes, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom; ​vrinda.​saraff@​nhs.​net Abstract Background Hypophosphatasia (HPP) is a rare inherited disorder affecting bone and teeth development. Perinatal HPP is the most severe form and associated with a high mortality. Features include respiratory distress, skeletal abnormalities and low alkaline phosphatase (ALP) activity. Case A baby boy developed respiratory distress, hypotonia and seizures within an hour of birth. Blood gas showed mixed acidosis and abnormal base deficit. Hypoxic–ischaemic encephalopathy (HIE) was suspected and managed with therapeutic hypothermia. Subsequent investigations identified low ALP activity and abnormal bone mineralisation, leading to a diagnosis of HPP. On day 5 of life, enzyme replacement therapy (ERT) was commenced, its first use via direct NHS England funding since UK licensing in 2017. Conclusions Early hypotonia is an atypical presentation for perinatal HPP. Combined with acidosis and encephalopathy, it can clinically mimic HIE. Early recognition of biochemical and radiological features of HPP is essential for rapid diagnosis and timely initiation of life-­saving ERT. Introduction © Author(s) (or their employer(s)) 2020. No commercial re-­use. See rights and permissions. Published by BMJ. To cite: Picton A, Nadar R, Pelivan A, et al. Arch Dis Child Epub ahead of print: [please include Day Month Year]. doi:10.1136/ archdischild-2019-317761 Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder which affects bone and teeth development by disrupting mineralisation. It is caused by loss-­of-­function mutations in the ALPL gene, which codes for the enzyme Tissue Nonspecific Alkaline Phosphatase (TNSALP).1 HPP is a continuum with a broad spectrum of severity. Six forms are delineated: perinatal severe, prenatal benign, infantile, childhood, adult and finally odontoHPP which is mild and affects dentition only.2 The wide phenotypic variability is due to over 200 recognised mutations.3 Perinatal severe HPP is the rarest type, affecting approximately 1 in 300 000 newborns.3 Inheritance is autosomal recessive, with carrier frequency estimated at 1/270.3 Clinical features include severe respiratory distress and seizures. Skeletal findings include hypomineralisation, bowed or short long bones, soft skull bones and fractures. These may be detected in utero.1 Respiratory distress is caused by chest deformities related to hypomineralisation and lung hypoplasia. Blood results demonstrate very low or absent alkaline phosphatase (ALP) activity. Treatment with enzyme replacement therapy (ERT) is now available as asfotase alfa (Strensiq; Alexion Pharmaceuticals) and was licensed for eligible patients by NHS England in 2017.4 Prior to ERT, perinatal severe HPP was mostly lethal due to respiratory complications.1 Hypoxic–ischaemic encephalopathy (HIE) is a much more common neonatal presentation than HPP, occurring in approximately 1.5–2/1000 births in developed countries.5 An acute or subacute perinatal shortage of oxygen and blood flow results in neurological depression at birth. Affected infants may present following prolonged resuscitation or with severe acidosis, accompanied by seizures or encephalopathy. We discuss a baby who presented with hypotonia, seizures and respiratory distress at birth. He was initially managed for suspected HIE until subsequent biochemical and radiological findings led to a diagnosis of perinatal HPP. Case We present the case of a 36+4weekgestation male baby born to a 25-­year-­old primigravida. Antenatal course was unremarkable except for detection of short femurs on foetal ultrasound scan at 34 weeks’ gestation. He was born via normal vaginal delivery with a birth weight of 3100 g. Apgar scores were 8 at 1 minute then 9 at both 5 and 10 minutes. He developed increasing respiratory distress with desaturations in the first hour of life. On examination, he was hypotonic with global hyporeflexia, a wide anterior fontanelle and a soft skull. There were no dysmorphic features or other bony deformities. He subsequently developed fever and seizure-­ like activity. Capillary blood gas showed a mixed respiratory and metabolic acidosis (pH 7.05 (7.35–7.45), PaCO2 9.18 (4.6–6.4 kPa), base excess −17.5 (−2 to +2 mmol/L), HCO3 −12.8 (14–28 mmol/L), lactate 13.9 mmol/L). Although at this point there was no evidence of a perinatal hypoxic event apart from a pathological cardiotocography (CTG) trace, therapeutic hypothermia was commenced in view of the infant presenting with features suggestive of neonatal encephalopathy such as seizures, abnormal tone and reflexes with decreased level of consciousness and respiratory depression within first hour of life. Despite treatment with 8 L of humidified high-­ flow oxygen via nasal cannulae, the baby deteriorated, requiring intubation and ventilation at 30 hours of age. Blood results showed an ALP of <5 IU/L. Chest X-­ ray showed gracile, undermineralised ribs. HPP was suspected on the basis of persistently low ALP activity combined with respiratory distress and radiological abnormalities. Skeletal survey demonstrated widespread skeletal Picton A, et al. Arch Dis Child 2020;0:1–3. doi:10.1136/archdischild-2019-317761    1 Arch Dis Child: first published as 10.1136/archdischild-2019-317761 on 22 January 2020. Downloaded from http://adc.bmj.com/ on January 30, 2020 at Agence Bibliographique de l Enseignement Superieur (ABES). Protected by copyright. Hypophosphatasia mimicking hypoxic–ischaemic encephalopathy: early recognition and management Short report undermineralisation and metaphyseal changes. He was transferred on day 4 of life to a paediatric intensive care unit in a tertiary centre which specialises in managing HPP. ERT was initiated and administered subcutaneously three times per week. He developed repeated clusters of short seizures on day 4 which responded to pyridoxine. MRI brain scan was normal apart from tiny foci of intracranial haemorrhage. Pre-­ ERT samples provided biochemical evidence of HPP with an elevated plasma pyridoxal-5-­ phosphate (PLP) level of 1182 nmol/L (normal range, 40–100) and urinary Figure 2 X-­rays at diagnosis showing undermineralisation with metaphyseal fraying and cupping of (A) left upper limb and (C) left lower limb. Comparative X-­rays following 3 months on enzyme replacement treatment demonstrating healing metaphyseal lesions of (B) left humerus and (D) left distal femur and tibia/fibula. 2 Discussion Prominent and early hypotonia is an atypical presentation of perinatal HPP. This is likely to have contributed to the initial respiratory acidosis owing to the poor respiratory effort in our case. Persistent poor oxygenation then quickly led on to mixed respiratory and metabolic acidosis. In a case series of 11 perinatal patients with HPP, only two exhibited early hypotonia and it was noted at a later time of 9 and 14 days of life in contrast to our case.6 More common causes of neonatal hypotonia include HIE, chromosomal abnormalities or a neurological disorder. In our case, very low ALP activity combined with skeletal survey findings were the key results that led away from a working diagnosis of HIE and towards HPP. Low ALP activity can also be associated with other conditions including sepsis, nutritional deficiencies, anaemia and hypothyroidism.2 As these conditions are often reversible, low ALP activity in these cases is usually a transient phenomenon. However, persistently low ALP activity must be followed up with further assessment for HPP even if asymptomatic.2 In general, a very low or undetectable ALP concentration at birth should raise a strong suspicion of a more severe form of HPP rather than an alternate cause. A diagnosis of HPP can be supported by measuring serum PLP which is a sensitive marker for HPP. An elevated urinary PEA offers additional supportive information although not pathognomonic for HPP.1 Both PLP and PEA are substrates for TNSALP. Genetic testing provides the definitive diagnosis.1 Early diagnosis facilitates prompt treatment with ERT. This case represents the first use of asfotase alfa in the perinatal period through direct NHS England funding (rather than compassionate use) since the drug was recommended for paediatric-­onset HPP by the National Institute for Health and Care Excellence in 2017.4 Asfotase alfa is a fusion protein containing recombinant human TNSALP that targets bone tissue. It is generally well tolerated with a good safety profile in the paediatric population. In multicentre studies, it demonstrates improvements in overall survival, ventilator-­ free survival, growth and bone mineralisation versus historical controls.7 Improved survival is the highest in patient subgroups at greatest risk of death, specifically those requiring ventilator support and/or pyridoxine-­responsive seizures, as PLP requires dephosphorylation prior to crossing the blood–brain barrier. Both these factors were present in our case, highlighting the importance of an early diagnosis.5 Picton A, et al. Arch Dis Child 2020;0:1–3. doi:10.1136/archdischild-2019-317761 Arch Dis Child: first published as 10.1136/archdischild-2019-317761 on 22 January 2020. Downloaded from http://adc.bmj.com/ on January 30, 2020 at Agence Bibliographique de l Enseignement Superieur (ABES). Protected by copyright. Figure 1 (A) Chest X-­ray before treatment—note thin and gracile ribs. (B) Chest X-­ray after 3 months on enzyme replacement therapy showing improved mineralisation of ribs. (C) Skull X-­ray at birth showing gross undermineralisation of skull vault. phosphoethanolamine (PEA) of 1546 μmol/mol creatinine (normal value <20). Genetic testing by whole-­exome sequencing identified the patient was compound heterozygous for the following ALPL missense variants: c.400_401delACinsCA p.(Thr134His), previously described as a disease-­causing variant; and c.1471G>A p.(Gly491Arg), previously described in association with severe HPP. It was later confirmed that he had inherited this from his parents. This combined with the clinical presentation confirmed the diagnosis of autosomal recessive HPP. Respiratory support was weaned and then stopped at 8 weeks of life. He was discharged home on full oral feeds and three times weekly ERT. He is currently gaining weight satisfactorily and has had no further seizures, fractures or nephrocalcinosis. He has shown excellent response to ERT with radiological improvement in metaphyseal changes, bone mineralisation and remodelling as evidenced in figures 1 and 2. On assessment of his development at 18 months, he is cruising around furniture but not walking independently yet. His fine motor skills are age appropriate and he has plenty of single words. Short report Perinatal HPP is very rare and has a high mortality if left untreated. Early detection is vital with a high index of suspicion required, particularly when presented with persistent and extremely low ALP activity. Prompt ERT can improve immediate and long-­term outcomes. These children should be managed in a tertiary centre with the required expertise. Contributors APi led the case report writing process. All authors reviewed the child’s clinical record for data extraction and contributed to the manuscript. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-­for-­profit sectors. Competing interests VS was a clinical study investigator and received honoraria and travel support from Alexion Pharmaceuticals for participation on advisory boards. Patient consent for publication Parental/guardian consent obtained. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data sharing not applicable as no datasets generated and/or analysed for this study. Picton A, et al. Arch Dis Child 2020;0:1–3. doi:10.1136/archdischild-2019-317761 ORCID iDs Aled Picton http://​orcid.​org/​0000-​0001-​9990-​2554 Vidya Garikapati http://​orcid.​org/​0000-​0002-​8420-​8057 Vrinda Saraff http://​orcid.​org/​0000-​0003-​3601-​8942 References 1 Mornet E. Hypophosphatasia. Metabolism 2018;82:142–55. 2 Saraff V, Narayanan VK, Lawson AJ, et al. A diagnostic algorithm for children with low alkaline phosphatase activities: lessons learned from laboratory screening for hypophosphatasia. J Pediatr 2016;172:181–6. 3 Mornet E, Yvard A, Taillandier A, et al. A molecular-­based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet 2011;75:439–45. 4 National Institute for Health and Care Excellence. Asfotase alfa for treating paediatric-­ onset hypophosphatasia (highly specialised technologies guidance HST6), 2017. 5 Greenwood A, Evans J, Smit E. New brain protection strategies for infants with hypoxic–ischaemic encephalopathy. Paediatr Child Health 2018;28:405–11. 6 Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-­replacement therapy in life-­ threatening hypophosphatasia. N Engl J Med 2012;366:904–13. 7 Whyte MP, Rockman-­Greenberg C, Ozono K, et al. Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia. J Clin Endocrinol Metab 2016;101:334–42. 3 Arch Dis Child: first published as 10.1136/archdischild-2019-317761 on 22 January 2020. Downloaded from http://adc.bmj.com/ on January 30, 2020 at Agence Bibliographique de l Enseignement Superieur (ABES). Protected by copyright. Conclusions