Scientific Letter
Hepatic involvement in a female carrier heterozygous for a mutation in the PHKA2 gene
Afectación hepática de paciente portadora en heterocigosis de una mutación en el gen PHKA2
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"tieneTextoCompleto" => true "saludo" => "Dear Editor:" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "267" "paginaFinal" => "268" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Teresa Blanco Sánchez, Elvira Cañedo Villarroya, Ana Martínez Zazo, Belén Pérez González, Consuelo Pedrón Giner" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Teresa" "apellidos" => "Blanco Sánchez" "email" => array:1 [ 0 => "teresablanc@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Elvira" "apellidos" => "Cañedo Villarroya" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Ana" "apellidos" => "Martínez Zazo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Belén" "apellidos" => "Pérez González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Consuelo" "apellidos" => "Pedrón Giner" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Sección de Gastroenterología y Nutrición, Hospital Infantil Universitario Niño Jesús, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital La Moraleja, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma Madrid, IdiPAZ. CIBERER, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Afectación hepática de paciente portadora en heterocigosis de una mutación en el gen <span class="elsevierStyleItalic">PHKA2</span>" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Glycogen storage diseases (GSDs) are a group of hereditary diseases characterised by abnormalities in glycogen metabolism. Glycogen storage disease type IX, which is caused by a defect in glycogen phosphorylase kinase (PHK), accounts for 25% of GSD cases, and the most frequent subtype is <span class="elsevierStyleItalic">PHKA2</span> (GSDIXa; OMIM: <a id="intr0010" class="elsevierStyleInterRef" href="omim:306000">306000</a>) with a recessive X-linked inheritance pattern.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> The phenotype of these patients ranges from mild forms presenting with hepatomegaly and elevation of liver enzyme levels to more severe forms that manifest with hypoglycaemia, short stature and mild gross motor delays.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> Other possible manifestations include high blood cholesterol, triglyceride levels and ketosis following breakfast.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> Symptoms usually improve with age, although some patients develop liver tissue fibrosis that may progress to cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">There are very few descriptions of females affected by GSDIXa in the literature, but those with heterozygous mutations may have disease manifestations in a wide spectrum.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> In these cases, X chromosome inactivation could play an important role in disease expression, although many other biological events are at play.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the clinical case of a girl whose relevant family history consisted of a brother with GSD type IXa and consanguinity (the father was the son of a first cousin of the mother). Onset in the brother occurred at age 14 months with abdominal distension, hepatomegaly, hypertransaminasemia and hypertriglyceridaemia and episodes of hypoglycaemia. A liver biopsy was performed, the results of which were compatible with GSD, followed by genetic testing that confirmed the diagnosis of GSDIXa with a hemizygous c.1404dupT mutation in gene <span class="elsevierStyleItalic">PHKA2</span>. His sister was seen in the office for the first time at age 4 months. Relevant findings in this visit included hepatomegaly, with the liver extending 3<span class="elsevierStyleHsp" style=""></span>cm below the costal margin, a reported absence of manifestations of hypoglycaemia, and adequate weight and height. Blood testing revealed elevated transaminase levels (GOT, 131<span class="elsevierStyleHsp" style=""></span>U/L; GPT 74<span class="elsevierStyleHsp" style=""></span>U/L) and levels of CPK, glucose, cholesterol and triglycerides within normal ranges. The evaluation was completed with an abdominal ultrasound scan, which showed diffuse changes in echogenicity in the liver. The patient was fitted with a transcutaneous 3-day continuous glucose-sensing system that did not detect any episodes of hypoglycaemia. During the follow-up period, hepatomegaly progressed to up to 5<span class="elsevierStyleHsp" style=""></span>cm along with an increase in transaminase levels, which peaked at 212<span class="elsevierStyleHsp" style=""></span>U/L for got and 144<span class="elsevierStyleHsp" style=""></span>U/L for GPT, while the patient remained asymptomatic. Genetic testing was ordered on account of the positive history of GSDIXa in her brother, confirming the presence of a heterozygous c.1404dupT mutation in the <span class="elsevierStyleItalic">PHKA2</span> gene. The patient was given dietary recommendations, including a maximum duration of 8<span class="elsevierStyleHsp" style=""></span>h for fasting periods and the intake of low-burning carbohydrates before bedtime. The patient remained asymptomatic during follow-up, with adequate physical and psychomotor growth and persistence of mild hypertransaminasaemia and hepatomegaly at nearly 3 years of age. Her brother had equally favourable outcomes, with catch-up growth in height from a <span class="elsevierStyleItalic">z</span>-score of −1.39 to a <span class="elsevierStyleItalic">z</span>-score of −0.11 in the last checkup at age 5 years. However, the brother did have recurrent episodes of hypoglycaemia, some of which even required overnight continuous enteral feeding due to his difficulty in achieving an adequate oral intake.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Diseases with a recessive X-linked pattern of inheritance usually produce symptoms only in males. In females, the molecular mechanism known as X chromosome inactivation, which consists of the random transcriptional silencing of one of the X chromosomes, inactivates either the healthy or the abnormal chromosome, and if the number of cells in which the normal gene is inactivated is higher, the disease may manifest.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> There is a published case of a female patient with a heterozygous c.3614C>T mutation in the <span class="elsevierStyleItalic">PHKA2</span> gene that presented with hepatomegaly and abnormal liver function during childhood, both of which normalised gradually. Molecular testing detected skewed X-chromosome inactivation in the patient, in contrast with a normal inactivation pattern in her sister, who had the same heterozygous mutation but remained asymptomatic.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Thus, it is important to perform carriage testing in females, as some of them may develop manifestations of GSDIXa of varying severity, which may be associated to the degree of skewed X chromosome inactivation,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> an association that has not been found in some studies of other X-linked hereditary disorders.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> It also makes genetic counselling possible.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Recently developed next generation sequencing (NGS) methods are now the gold standard for confirming the diagnosis of GSDs, replacing the invasive methods used in the past, such as liver biopsy.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Blanco Sánchez T, Cañedo Villarroya E, Martínez Zazo A, Pérez González B, Pedrón Giner C. Afectación hepática de paciente portadora en heterocigosis de una mutación en el gen <span class="elsevierStyleItalic">PHKA2</span>. An Pediatr (Barc). 2016;85:267–268.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical, biochemical, and genetic characterization of glycogen storage type ix in a child with asymptomatic hepatomegaly" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.A. Kim" 1 => "J.H. Kim" 2 => "B.H. Lee" 3 => "G.H. Kim" 4 => "Y.S. Shin" 5 => "H.W. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 7 | 11 |
| 2024 October | 54 | 32 | 86 |
| 2024 September | 41 | 30 | 71 |
| 2024 August | 77 | 59 | 136 |
| 2024 July | 48 | 28 | 76 |
| 2024 June | 67 | 33 | 100 |
| 2024 May | 49 | 33 | 82 |
| 2024 April | 56 | 29 | 85 |
| 2024 March | 53 | 21 | 74 |
| 2024 February | 42 | 27 | 69 |
| 2024 January | 28 | 20 | 48 |
| 2023 December | 53 | 21 | 74 |
| 2023 November | 59 | 25 | 84 |
| 2023 October | 30 | 20 | 50 |
| 2023 September | 19 | 17 | 36 |
| 2023 August | 30 | 21 | 51 |
| 2023 July | 30 | 26 | 56 |
| 2023 June | 28 | 22 | 50 |
| 2023 May | 34 | 16 | 50 |
| 2023 April | 18 | 24 | 42 |
| 2023 March | 38 | 23 | 61 |
| 2023 February | 30 | 13 | 43 |
| 2023 January | 19 | 28 | 47 |
| 2022 December | 43 | 23 | 66 |
| 2022 November | 59 | 28 | 87 |
| 2022 October | 60 | 44 | 104 |
| 2022 September | 39 | 67 | 106 |
| 2022 August | 42 | 72 | 114 |
| 2022 July | 30 | 41 | 71 |
| 2022 June | 34 | 32 | 66 |
| 2022 May | 29 | 36 | 65 |
| 2022 April | 39 | 40 | 79 |
| 2022 March | 90 | 45 | 135 |
| 2022 February | 45 | 28 | 73 |
| 2022 January | 58 | 32 | 90 |
| 2021 December | 45 | 38 | 83 |
| 2021 November | 53 | 48 | 101 |
| 2021 October | 54 | 69 | 123 |
| 2021 September | 27 | 41 | 68 |
| 2021 August | 28 | 45 | 73 |
| 2021 July | 26 | 23 | 49 |
| 2021 June | 21 | 35 | 56 |
| 2021 May | 38 | 33 | 71 |
| 2021 April | 97 | 49 | 146 |
| 2021 March | 41 | 32 | 73 |
| 2021 February | 39 | 16 | 55 |
| 2021 January | 42 | 25 | 67 |
| 2020 December | 26 | 25 | 51 |
| 2020 November | 28 | 16 | 44 |
| 2020 October | 32 | 22 | 54 |
| 2020 September | 25 | 21 | 46 |
| 2020 August | 20 | 17 | 37 |
| 2020 July | 22 | 18 | 40 |
| 2020 June | 40 | 14 | 54 |
| 2020 May | 27 | 22 | 49 |
| 2020 April | 34 | 24 | 58 |
| 2020 March | 21 | 18 | 39 |
| 2020 February | 26 | 22 | 48 |
| 2020 January | 22 | 16 | 38 |
| 2019 December | 22 | 20 | 42 |
| 2019 November | 21 | 12 | 33 |
| 2019 October | 31 | 20 | 51 |
| 2019 September | 22 | 8 | 30 |
| 2019 August | 48 | 24 | 72 |
| 2019 July | 36 | 22 | 58 |
| 2019 June | 36 | 16 | 52 |
| 2019 May | 47 | 34 | 81 |
| 2019 April | 87 | 33 | 120 |
| 2019 March | 32 | 17 | 49 |
| 2019 February | 41 | 18 | 59 |
| 2019 January | 29 | 26 | 55 |
| 2018 December | 37 | 25 | 62 |
| 2018 November | 99 | 29 | 128 |
| 2018 October | 95 | 21 | 116 |
| 2018 September | 38 | 10 | 48 |
| 2018 August | 2 | 0 | 2 |
| 2018 June | 3 | 0 | 3 |
| 2018 May | 5 | 0 | 5 |
| 2018 April | 35 | 0 | 35 |
| 2018 March | 68 | 0 | 68 |
| 2018 February | 19 | 0 | 19 |
| 2018 January | 81 | 0 | 81 |
| 2017 December | 74 | 0 | 74 |
| 2017 November | 28 | 0 | 28 |
| 2017 October | 17 | 0 | 17 |
| 2017 September | 14 | 0 | 14 |
| 2017 August | 14 | 0 | 14 |
| 2017 July | 17 | 0 | 17 |
| 2017 June | 24 | 12 | 36 |
| 2017 May | 23 | 17 | 40 |
| 2017 April | 27 | 19 | 46 |
| 2017 March | 21 | 5 | 26 |
| 2017 February | 6 | 11 | 17 |
| 2017 January | 10 | 10 | 20 |
| 2016 December | 20 | 12 | 32 |
| 2016 November | 30 | 22 | 52 |
| 2016 October | 11 | 13 | 24 |
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