Impact of a modification of the clinical practice guide of the American Academy of Pediatrics in the management of severe acute bronchiolitis in a pediatric intensive care unit.

OBJECTIVE: To describe the characteristics and evolution of patients with bronchiolitis admitted to a pediatric intensive care unit, and compare treatment pre- and post-publication of the American Academy of Pediatrics clinical practice guide. DESIGN: A descriptive and observational study was carried out between September 2010 and September 2017. SETTING: Pediatric intensive care unit. PATIENTS: Infants under one year of age with severe bronchiolitis. INTERVENTIONS: Two periods were compared (2010-14 and 2015-17), corresponding to before and after modification of the American Academy of Pediatrics guidelines for the management of bronchiolitis in hospital. MAIN VARIABLES: Patient sex, age, comorbidities, severity, etiology, administered treatment, bacterial infections, respiratory and inotropic support, length of stay and mortality. RESULTS: A total of 706 patients were enrolled, of which 414 (58.6%) males, with a median age of 47 days (IQR 25-100.25). Median bronchiolitis severity score (BROSJOD) upon admission: 9 points (IQR 7-11). Respiratory syncytial virus appeared in 460 (65.16%) patients. The first period (2010-14) included 340 patients and the second period (2015-17) 366 patients. More adrenalin and hypertonic saline nebulizations and more corticosteroid treatment were administered in the second period. More noninvasive ventilation and less conventional mechanical ventilation were used, and less inotropic support was needed, with no significant differences. The antibiotherapy rate decreased significantly (p=0.003). CONCLUSIONS: Despite the decrease in antibiotherapy, the use of nebulizations and glucocorticoids in these patients should be limited, as recommended by the guide.

Impact of a modification of the clinical practice guide of the American Academy of Pediatrics in the management of severe acute bronchiolitis in a pediatric intensive care unit. / Impacto de una modificación de la guía de práctica clínica de la Academia Americana de Pediatría en el manejo de la bronquiolitis aguda grave en una unidad de cuidados intensivos pediátricos.

OBJECTIVE: To describe the characteristics and evolution of patients with bronchiolitis admitted to a pediatric intensive care unit, and compare treatment pre- and post-publication of the American Academy of Pediatrics clinical practice guide. DESIGN: A descriptive and observational study was carried out between September 2010 and September 2017. SETTING: Pediatric intensive care unit. PATIENTS: Infants under one year of age with severe bronchiolitis. INTERVENTIONS: Two periods were compared (2010-14 and 2015-17), corresponding to before and after modification of the American Academy of Pediatrics guidelines for the management of bronchiolitis in hospital. MAIN VARIABLES: Patient sex, age, comorbidities, severity, etiology, administered treatment, bacterial infections, respiratory and inotropic support, length of stay and mortality. RESULTS: A total of 706 patients were enrolled, of which 414 (58.6%) males, with a median age of 47 days (IQR 25-100.25). Median bronchiolitis severity score (BROSJOD) upon admission: 9 points (IQR 7-11). Respiratory syncytial virus appeared in 460 (65.16%) patients. The first period (2010-14) included 340 patients and the second period (2015-17) 366 patients. More adrenalin and hypertonic saline nebulizations and more corticosteroid treatment were administered in the second period. More noninvasive ventilation and less conventional mechanical ventilation were used, and less inotropic support was needed, with no significant differences. The antibiotherapy rate decreased significantly (P=.003). CONCLUSIONS: Despite the decrease in antibiotherapy, the use of nebulizations and glucocorticoids in these patients should be limited, as recommended by the guide.

[More than three hours, less than three years. Safety of anesthetic procedures in children under three years, subject to surgeries of more than three hours]. / Más de tres horas y menos de tres años. Seguridad de procedimientos anestésicos en niños menores de tres años, sometidos a cirugías de más de tres horas.

The Food and Drug Administration (USA) warning (December 2016) on the safety of general anesthesia and sedation in patients younger that 3 years and pregnant women has raised many questions about the attitude that should be taken by professionals involved in the treatment of these patients. In view of this situation, the following Medical Scientific Societies: SEDAR, SECP, SECIP and SENeo have constituted a working group to analyze and clarify the safety of these techniques. In the present article, we conclude that at present both general anesthesia and deep sedation should continue to be considered safe techniques because there is no sufficient opposing evidence in clinical studies with humans. Despite this, we should not ignore the problem which must be followed carefully mainly in patients under three years of age undergoing anesthetic procedures longer than three hours or prolonged sedation in Neonatal or Pediatric Intensive Care Units.

La alerta de la FDA de diciembre 2016, sobre la seguridad de la anestesia general y las sedaciones en pacientes menores de 3 años y en mujeres embarazadas, ha suscitado numerosas dudas sobre la actitud que deben tomar los profesionales implicados en el tratamiento de estos pacientes. Ante esta situación, las siguientes Sociedades Científicas Médicas: SEDAR (Sociedad Española de Anestesia y Reanimación), SECP (Sociedad Española de Cirugía Pediátrica), SECIP (Sociedad Española de Cuidados Intensivos Pediátricos) y SENeo (Sociedad Española de Neonatología), han constituido un grupo de trabajo para analizar y clarificar la seguridad de estas técnicas. En este artículo concluimos que en el momento actual tanto la anestesia general como la sedación profunda deben seguir siendo consideradas como técnicas seguras, porque no existen evidencias de lo contrario en estudios con seres humanos. Esta seguridad no nos permite ignorar el problema, que debe ser seguido con atención, fundamentalmente en pacientes de menos de tres años, sometidos a procedimientos anestésicos de más de tres horas o a sedaciones prolongadas en las Unidades de Cuidados Intensivos Neonatales o Pediátricos.

Utilización de la craniectomía descompresiva en el manejo de la hipertensión intracraneal refractaria en la edad pediátrica / Use of decompressive craniectomy in the management of refractory intracranial hypertension in paediatric patients

Introducción y objetivo: La hipertensión intracraneal (HITC) es la principal causa de mortalidad y secuelas de los pacientes con traumatismo craneoencefálico grave. La craniectomía descompresiva (CD) es una técnica quirúrgica que permite disminuir la presión intracraneal y mejorar la presión de perfusión cerebral (PPC). El objetivo del trabajo es presentar la experiencia con la CD para el tratamiento de la hipertensión intracraneal. Pacientes y métodos: Revisión retrospectiva de los pacientes ingresados entre los años 2005–2008 con lesión cerebral e hipertensión intracraneal incontrolable médicamente a los que se les realizó una CD como terapia. Resultados: Se incluyen 14 pacientes con traumatismo craneoencefálico grave con una mediana de edad de 14,2 años (4–20 años). Las lesiones detectadas más frecuentemente en la TC craneal de los niños con traumatismo fueron las lesiones encefálicas difusas II y III. En todos se practicó una CD por presentar cifras de presión intracraneal elevadas refractarias a la terapéutica instaurada. La evolución fue favorable en todos los pacientes salvo en 2. El 78,8% presenta una buena evolución neurológica (Glasgow Outcome Score 4 y 5) a los 6 meses de la intervención. Conclusión: La CD es una alternativa en el manejo de la hipertensión intracraneal refractaria al tratamiento médico en niños y adolescentes que han sufrido un traumatismo craneoencefálico grave y puede ser usada simultáneamente o como alternativa al coma barbitúrico sobre todo en aquellos pacientes con inestabilidad hemodinámica (AU)

Introduction and objective: Intracranial hypertension (ICH) is the main cause of morbidity and mortality in patients with severe traumatic head injuries. Decompressive craniectomy (DC) is a surgical technique that allows to reduce intracranial pressure (ICP) and to improve cerebral blood flow. Objective: To present our experience on DC for the treatment of ICH. Patients and methods: Retrospective review of patients admitted from January 2005 to December 2008 who had a traumatic brain injury (TBI) and uncontrollable intracranial hypertension despite optimal medical treatment and who needed DC. Results: Fourteen patients with severe TBI were included in this series. Mean age was 14.2 years (4–20 years). The more frequent damages detected in cranial computerized tomography were diffuse brain lesions types II and III. Indication for DC was made if ICP levels were above 25mmHg for more than 30min despite optimal medical treatment. Clinical outcome was favourable in all patients apart from two. Neurological outcome was correct in 78.8% of patients (Glasgow Outcome Score 4 and 5) six months after PICU discharge. Conclusion: DC is an alternative for the management of refractory intracranial hypertension in children and adolescents with severe TBI. It could be used simultaneously with the barbiturate coma or as an alternative, particularly in haemodynamically unstable patients (AU)

[Use of decompressive craniectomy in the management of refractory intracranial hypertension in paediatric patients]. / Utilización de la craniectomía descompresiva en el manejo de la hipertensión intracraneal refractaria en la edad pediátrica.

INTRODUCTION AND OBJECTIVE: Intracranial hypertension (ICH) is the main cause of morbidity and mortality in patients with severe traumatic head injuries. Decompressive craniectomy (DC) is a surgical technique that allows to reduce intracranial pressure (ICP) and to improve cerebral blood flow. OBJECTIVE: To present our experience on DC for the treatment of ICH. PATIENTS AND METHODS: Retrospective review of patients admitted from January 2005 to December 2008 who had a traumatic brain injury (TBI) and uncontrollable intracranial hypertension despite optimal medical treatment and who needed DC. RESULTS: Fourteen patients with severe TBI were included in this series. Mean age was 14.2 years (4-20 years). The more frequent damages detected in cranial computerized tomography were diffuse brain lesions types II and III. Indication for DC was made if ICP levels were above 25 mmHg for more than 30 min despite optimal medical treatment. Clinical outcome was favourable in all patients apart from two. Neurological outcome was correct in 78.8% of patients (Glasgow Outcome Score 4 and 5) six months after PICU discharge. CONCLUSION: DC is an alternative for the management of refractory intracranial hypertension in children and adolescents with severe TBI. It could be used simultaneously with the barbiturate coma or as an alternative, particularly in haemodynamically unstable patients.

Métodos diagnósticos complementarios: ¿cuál es su utilidad clínica real en las encefalitis herpéticas? / Complementary diagnostic methods: which is their actual clinical utility in herpetic encephalitis?

Objetivos: Caracterizar la forma de presentación clínica de laencefalitis herpética y comprobar la utilidad de las diferentesexploraciones complementarias en su manejo.Material y métodos: Revisión retrospectiva de los casos deencefalitis herpética, diagnosticados mediante reacción en cadenade la polimerasa (PCR) cuantitativa, que requirieron ingresoen unidades de cuidados intensivos pediátricas. Se recogierondatos acerca de la evolución clínica y la sensibilidad de losdiferentes métodos diagnósticos complementarios. En 7 casosse reevaluó el líquido cefalorraquídeo (LCR) mediante cuantificaciónde ADN por PCR y se correlacionó la carga viral con losdiferentes datos clínicos.Resultados: En total se detectaron 16 casos. El rango deedad osciló entre los 19 días y los 12 años (edad media: 34meses). La forma de presentación clínica fue indiferenciable dela presentada por otras encefalitis, y predominó la existenciade fiebre (en un 81% de los casos), convulsiones (68%), vómitos(62%) y disminución del nivel de conciencia (50%). La sensibilidadde la neuroimagen y los estudios neurofisiológicosfue inferior al 80% (e inferior al 50% en las primeras 24 horasdel cuadro). Observamos una excelente sensibilidad de la PCRcuantitativa en el diagnóstico y la detección de la carga viral.Se correlacionó positivamente de forma estadísticamente significativala carga viral con la edad del paciente, el número deleucocitos en el LCR y el tiempo de evolución del cuadro. Nohubo correlación entre la carga viral y el pronóstico de la enfermedad(AU)

Conclusiones: Ni la presentación clínica, ni la neuroimagen ni los estudios neurofisiológicos disponen de una sensibilidad suficiente como para orientar el diagnóstico. Por el contrario, la PCR cuantitativa a tiempo real sí es sensible para el diagnóstico de la encefalitis herpética. No se ha correlacionado la carga viral con el pronóstico, aunque son necesarios más estudios para evaluar la utilidad clínica de esta técnica (AU)

Objectives: Depict the form of the clinical manifestation of the herpetic encephalitis and prove the utility of the different complementary explorations in its use. Material and methods: Retrospective revision of the herpeticencephalitis cases diagnosed through quantitative PCR which required to be admitted in UCIP (Intensive Care and Pediatric Urgencies). There was a collection of data regarding the clinical evolution and the sensitivity of the different complementary diagnostic methods. In the 7 cases the LCR was reevaluated through DNA quantification by means of PCR and the viral load was correlated with the different clinical data. Results: 16 cases altogether. Their ages ranged between 19 days and 12 years (mean age: 34 months). The clinical manifestation was undistinguishable of the presented by other encephalitis. Main symptoms were fever (81% of the cases), convulsions (68%), vomiting (62%) and diminished level of consciousness (50%). Imaging tests and neurophysiological studies sensitivity were less than 80% (being less than 50% in the first 24 hours since the symptoms onset). Quantitative PCR is the gold standard for the detection of viral load. Viral load was positively correlated with age, number of leukocytes in CSF and time since beginning of the clinical manifestation. There was no correlation between viral load and disease prognosis. Conclusions: Neither the clinical presentation or neuroimaging or neurophysiological studies have enough sensitivity for helping diagnosis. On the contrary, we have found that realtime quantitative PCR is useful for the diagnosis of herpeticencephalitis. There was no association between viral load and illness prognosis. The viral load has not been correlated with the clinical picture. However, more studies are needed to evaluate the clinical utility of this technique (AU)

[Preliminary clinical experience with PiCCO system in children with shock]. / Experiencia clínica de monitorización hemodinámica del shock mediante el sistema PiCCO.

PURPOSE: To evaluate the PiCCO hemodynamics monitor in terms of clinical usefulness in children with shock. METHODS: Prospective multicenter analytical study in children aged from one month to 18 years with shock admitted to five pediatric intensive care units. Measurements were made before and after three interventions: a) volume load; b) increases in vasoactive drugs; c) dosage changes of drugs that could lessen vascular resistance. Recorded parameters included thermodilution data, along with the usual hemodynamic parameters. RESULTS: A total of 120 measurements were performed on 35 patients: mean age 36 (2.6-156) months, mean weight 15 (5.8-72) kg. Shock etiology was septic in 37% of cases, cardiogenic in 26%, hypovolemic in 20% and neurogenic in 17%. No procedure related complication was noticed. Twenty-two volume challenges in 17 patients were registered. Volume load induced a significant intrathoracic blood volume index (ITBI) increase from 501(235-763) to 584 (418-810) ml/m(2), cardiac index (CI) 4.04 (2.58-6.25) to 4.48 (2.86-8.71) lmin-1m(2), and mean blood pressure from 74 (53-99) to 87 (59-112) mmHg. CI changes correlated with ITBI increase (r = 0.678, p = 0.001). 13 interventions to increase vasomotor tone were associated with an increase in contractility of 18% in systemic vascular resistance index (SVRI). CONCLUSIONS: Hemodynamic monitoring with the PiCCO system is feasible and seems safe in children with shock. PiCCO derived parameters could add clinically important information to assess preload state and its modifications with therapy.

[ECMO: experience in paediatrics]. / ECMO: experiencia en edad pediátrica.

INTRODUCTION: ECMO (Extracorporeal Membrane Oxygenation) provides a vital support to patients with supposed reversible respiratory and/or cardiac failure, in whom conventional support techniques have been previously unsuccessful. OBJECTIVES: To determinate the criteria used in our hospital to put paediatric patients on ECMO, compare their clinical course depending on their pathology (respiratory failure, congenital heart disease or sepsis) and identify the sequelae attributable to this technique. MATERIAL AND METHOD: A retrospective review of clinical records of all patients on ECMO support in our centre, excluding those presenting typically in neonatal period. RESULTS: ECMO was used on 16 patients from June 2001 to January 2007, of which 50% were males. The median age was 7 months (from 21 days to 11 years). The reason for starting ECMO was respiratory failure in 11 cases (oxygenation index >40 and/or alveolar-arterial oxygen gradient >605), congenital heart disease in 2 and sepsis in 3 (due to shock unresponsive to adequate resuscitation). The median time to starting ECMO from PICU admission was 3.58 days (from 12h to 9 days). Venovenous cannulation was used initially in 8 patients, but 5 of them needed venoarterial ECMO later. The technique was used for a mean of 8 days (from 1 to 28 days). The main complication was the isolation of bacteria in different cultures (8 patients). The overall survival was 50% (6 patients with respiratory failure and both patients submitted to cardiac surgery). Extracorporeal support was withdrawn in 7 children because their clinical situation was irreversible. Another patient died seven days after successful decannulation. We have not found any serious sequel among survivors that could be attributable to this technique. CONCLUSIONS: Survival among children supported with ECMO in our hospital is similar to that recorded by the ELSO in 2004, although the prognosis depends on the initial pathology. There are different criteria for starting this technique depending on the underlying diseases: respiratory index of poor prognosis in patients with respiratory failure, haemodynamic instability in those with sepsis or cardiac failure after cardiovascular surgery. We have not found any serious sequel among the survivors which could be attributable to this technique.

Do adult patients with phenylketonuria improve their quality of life after introduction/resumption of a phenylalanine-restricted diet?

AIM: To evaluate the possible influence of dietary treatment on the quality of life of adult patients with PKU (phenylketonuria) following late introduction or resumption of a Phe-restricted diet. METHODS: Fifteen adult patients with classical PKU (10F, 5M; mean age: 27.5 y, range: 16.4-37.5 y) were selected for the study. These patients had either resumed a restricted diet after a period of discontinuation, or were placed on a restricted diet after late diagnosis. All of them were interviewed about their quality of life using a 24-item questionnaire. RESULTS: The index of dietary control was poor (median Phe: 954 micromol/L) in 8/15 patients, regular (Phe: 514 micromol/L) in 4/15 and good (Phe: 354 micromol/L) in 3/15 patients. Fifty-three percent of patients reported that their state of health was very good, 47% described it as good, and 40% felt that their present health on-diet was better than it had been off-diet; 53% believed that they were calmer, quieter and less easily upset and 40% were more alert and were more able to maintain attention while on-diet. Thirty-three percent of the patients felt happier, and 27% felt more vital; 20% thought that they were less impulsive and aggressive, and that they were now less argumentative than before. Sixty percent of the patients felt that their quality of life had improved on-diet compared with the situation off-diet. CONCLUSION: More than half of our patients believed that their quality of life improved with a Phe-restricted diet; they reported feeling calmer, quieter, and less easily upset. Only 47% attained regular to good dietary control.

New approach to osteopenia in phenylketonuric patients.

AIM: To study bone mineralization in a group of phenylketonuric patients and to search for a possible relationship between bone mineral density, dietary control, serum minerals and nutrition intake. The response to treatment with low-dose 1.25-(OH)2 vitamin D in patients with osteopenia was evaluated. METHODS: Twenty-eight phenylketonuric patients (age range: 10-33 y) on dietary treatment were investigated. Bone density at the lumbar spine (Dual Energy X-ray Absorptiometry), bone formation markers (osteocalcin and bone alkaline phosphatase), serum minerals, index of dietary control and protein, vitamin D and mineral intakes were determined. RESULTS: Of the patients studied, 78.6% had good dietary compliance (462 +/- 89 micromol/L). Mean protein, vitamin D and mineral intakes met the recommended dietary allowances (RDAs). Nevertheless, 8 patients had calcium intakes lower than 1000 g/d, and a positive correlation between Z-score and calcium (r = 0.585; p = 0.002) or phosphorus intake (r = 0.546; p = 0.005) was observed. Osteopenia was detected in 14 patients (50%). Moreover, bone alkaline phosphatase in phenylketonuric patients older than 18 y of age was significantly lower than that in controls (p < 0.0001). No correlation was found between bone mineral density, age, serum minerals, bone formation markers or index of dietary control. Treatment with 0.25 microg/d calcitriol significantly increased bone density in 6 patients. CONCLUSION: A defect in bone mineralization was detected in 50% of patients in our series. The correct amount of formula intake seems to be necessary for bone mineralization in phenylketonuric patients. Calcitriol can be a useful treatment for these patients, although more studies are needed to confirm these results. Hypercalcaemia and hypercalciuria need to be carefully monitored.

Use of the Pediatric Risk of Mortality Score as predictor of death and serious neurologic damage in children after submersion.

OBJECTIVE: To evaluate the Pediatric Risk of Mortality score (PRISM score) as a tool to evaluate the vital and neurologic prognosis of patients after submersion. METHODS: We conducted a retrospective analysis of the clinical histories of patients admitted to a tertiary pediatric hospital, Hospital Sant Joan de Déu, Barcelona, Spain from December 1977 to December 1999 as a consequence of near-drowning. PRISM score was calculated for each patient with data obtained upon arrival at the hospital. The probability of death was calculated using this score. RESULTS: There were 60 patients, divided into two groups as they were admitted to the Pediatric Intensive Care Unit (PICU group, n = 41) or to the Short Stay Unit (SSU group, n = 19). All patients in the SSU group survived without impairments, with PRISM scores or=24 or with probability of death >or=42% either died or had serious neurologic impairment. One third of patients with PRISM scores between 17 and 23 and/or probability of death between 16 and 42% either presented serious neurologic impairment or died. CONCLUSIONS: PRISM score enables the determination of either absence or presence of serious impairment or death in pediatric patients after submersion, if they present extreme values on this scale. However, in patients with intermediate PRISM scores, it is not possible to establish a reliable prognosis.

Plasma phenylalanine is associated with decreased serum ubiquinone-10 concentrations in phenylketonuria.

Decreased serum ubiquinone-10 concentrations is a common condition in patients with phenylketonuria (PKU) under dietary treatment. Our aim was to investigate the implication of the metabolic abnormalities of PKU (low concentrations of tyrosine and high concentrations of phenylalanine) and the effect of treatment with phenylalanine-restricted diets in decreased ubiquinone-10 concentrations in PKU patients. We studied 30 PKU patients (age range 5 months to 35 years; median age 7 years) under dietary treatment. Correlation between plasma tyrosine or phenylalanine and serum ubiquinone-10 concentrations was investigated. Daily cholesterol intake was calculated from the data obtained through a dietary questionnaire. The index of dietary control (IDC) was calculated as the average of the medians of plasma phenylalanine concentrations obtained every 6 months in the metabolic control of patients. Negative correlations were observed between serum ubiquinone and the IDC (r=-0.46; p<0.01) in PKU patients. No correlation was observed between tyrosine or daily cholesterol intake and serum ubiquinone concentrations. After adjustment for daily cholesterol intake by multiple linear regression analysis, for each 113 units of increase in IDC values serum ubiquinone decreased 0.1 micromol/L. According to our results, the main factor associated with the decreased serum ubiquinone concentrations was high plasma phenylalanine values. Although daily cholesterol intake seems to be associated with ubiquinone concentrations, it may not be relevant if we take into account the low intake of cholesterol in treated PKU patients.

Is there a relationship between plasma phenylalanine and cholesterol in phenylketonuric patients under dietary treatment?

OBJECTIVES: To study the lipid profile in a group of treated phenylketonuric patients (PKU; n = 61) compared with a group of inborn error of intermediary metabolism patients (IEM; n = 22), a group of hyperphenylalaninemic children (HPA; n = 37), and a control group without dietary restriction (n = 41). DESIGN AND METHODS: Phenylalanine was analyzed by ion exchange chromatography and triglycerides, cholesterol and HDL were determined by standard procedures with the Cobas Integra analyzer. RESULTS: Serum total cholesterol concentrations were significantly lower in PKU patients compared with IEM patients (whose cholesterol daily intake was similar to those of PKU patients), HPA children and the control group. A negative correlation was observed between cholesterol and phenylalanine concentrations in the PKU patients. CONCLUSIONS: Our findings support the hypothesis of a relationship between high plasma phenylalanine levels and an inhibition of cholesterogenesis, although the low cholesterol intake of the special diets may also decrease serum cholesterol values.

Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes.

Phenylketonuria is one of the most common genetic diseases in humans, affecting 1 in 10,000 whites. Deletions are generally uncommon in genes in which no long highly homologous segments are present, and in phenylalanine hydroxylase (PAH) deficiency they represent only 5% of cases. We present the case of a girl affected by classical phenylketonuria who has been screened for mutations in the PAH gene. During the molecular study a large de novo deletion has detected in 12qter, including PAH, and the genes for insulin-like growth factor 1 (IGF1), human achaete-scute homolog 1 (ASCL1), and tumor rejection antigen (TRA1). The patient showed phenylketonuria, short stature, and pathological electro-oculography results in both eyes, with high affectation of the relative electrogenesis of the photoreceptor-pigment epithelium complex. She had previously been misdiagnosed as homozygous for the IVS8nt-7A-G mutation, instead of heterozygous for a mutation and a de novo deletion. As a result incorrect genetic counseling had been given. The deletion of the PAH, IGF1, and ASCL1 genes could explain the patient's phenotype corresponding to a contiguous gene syndrome. We stress the relevance of polymorphic marker haplotype analysis and the importance of family study in genetic recessive diseases, such as phenylketonuria, to avoid incorrect diagnosis and genetic counseling.