Expanding the phenotype of PIGP deficiency to multiple congenital anomalies-hypotonia-seizures syndrome.

Glycosylphosphatidylinositol-anchored proteins are involved in multiple physiological processes and the initial stage of their biosynthesis is mediated by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, and DMP2 genes, which have been linked to a wide spectrum of phenotypes depending on the gene damaged. To date, the PIGP gene has only been related to Developmental and Epileptic Encephalopathy 55 (MIM#617599) in just seven patients. A detailed medical history was performed in two affected siblings with a multiple malformation syndrome. Genetic testing was performed using whole-exome sequencing. One patient presented dysmorphic features, congenital anomalies, hypotonia and epileptic encephalopathy as described in PIGA, PIGQ and PIGY deficiencies. The other one was a fetus with a severe malformation disorder at 17 weeks of gestation whose pregnancy was interrupted. Both were compound heterozygous of pathogenic variants in PIGP gene: NM_153682.3:c.2 T > C(p.?) and a 136 Kb deletion (GRCh37/hg19 21q22.13(chr21:38329939-38 466 066)×1) affecting the entire PIGP gene. Our results extend the clinical phenotype associated to PIGP gene and propose to include it as a novel cause of Multiple Congenital Anomalies-Hypotonia-Seizures syndrome.

Acondroplasia: actualización en diagnóstico, seguimiento y tratamiento / Achondroplasia: Update on diagnosis, follow-up and treatment

La acondroplasia requiere un seguimiento multidisciplinario, con el objetivo de prevenir y manejar las complicaciones, mejorar la calidad de vida y favorecer su independencia e inclusión social. Esta revisión se justifica por las múltiples publicaciones generadas en los últimos años que han llevado a cabo un cambio en su gestión. Se han desarrollado diferentes guías y recomendaciones, entre las que destacan la realizada por la Academia Americana de Pediatría en 2005 recientemente actualizada (2020), la guía japonesa (2020), el primer Consenso Europeo (2021) y el Consenso Internacional sobre el diagnóstico, abordaje, enfoque multidisciplinario y manejo de individuos con acondroplasia a lo largo de la vida (2021). Sin embargo, y a pesar de estas recomendaciones, actualmente existe una gran variabilidad a nivel mundial en el manejo de las personas con acondroplasia, con consecuencias médicas, funcionales y psicosociales en los pacientes y sus familias. Por ello, es fundamental integrar estas recomendaciones en la práctica clínica diaria, teniendo en cuenta la situación particular de cada sistema sanitario. (AU)

Achondroplasia requieres a multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life and favoring their independence and social inclusion. This review is justified by the multiple publications generated in recent years that have carried out a change in its management. Different guidelines and recommendations have been developed, among which the one made by the American Academy of Pediatrics in 2005 recently updated (2020), the Japanese guide (2020), the first European Consensus (2021) and the International Consensus on the diagnosis, approach multidisciplinary approach and management of individuals with achondroplasia throughout life (2021). However, and despite these recommendations, there is currently a great worldwide variability in the management of people with achondroplasia, with medical, functional and psychosocial consequences in patients and their families. Therefore, it is essential to integrate these recommendations into daily clinical practice, taking into account the particular situation of each health system. (AU)

Criterios de derivación a genética clínica desde Atención Primaria. Documento de consenso / Referral criteria to clinical genetics from primary care: Consensus document

Introducción: La Atención Primaria (AP) es el primer contacto entre el paciente y el médico, por lo que es fundamental tener claro los criterios de sospecha de una enfermedad genética y dónde se debe remitir para su estudio. Material y métodos: Cuatro sociedades científicas: la Sociedad Española de Medicina Familiar y Comunitaria (semFYC), la Asociación Española de Genética Humana (AEGH), la Asociación Española de Pediatría (AEP) y la Sociedad Española de Oncología Médica (SEOM), han revisado los criterios de derivación a los servicios de genética clínica de las diferentes guías publicadas, con el objetivo de elaborar unas recomendaciones para AP. Conclusiones: Con este Documento de Consenso el médico de familia y el pediatra de AP conocerán cuándo, cómo y dónde derivar a sus pacientes con patología hereditaria y/o genética a los servicios de genética clínica.(AU)

Introduction: Primary care (PC) is the first contact between the patient and the doctor, so it is essential to be clear about the criteria for suspecting a genetic disease and where it should be referred for study. Material and methods: Four scientific societies: the Spanish Society of Family and Community Medicine (semFYC), the Spanish Association of Human Genetics (AEGH), the Spanish Association of Pediatrics (AEP) and the Spanish Society of Medical Oncology (SEOM), have reviewed the criteria for referral to the clinical genetics services of the different published guidelines with the purpose of define the recommendations for PC. Conclusions: With this consensus document, the PC doctor and pediatrician will know when, how and where to refer their patients with hereditary and/or genetic pathology to clinical genetics services.(AU)

Achondroplasia: Update on diagnosis, follow-up and treatment.

Achondroplasia requieres multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life of people who suffer from it and favoring their independence and social inclusion. This review is justified by the multiple publications generated in recent years that have carried out a change in its management. Different guidelines and recommendations have been developed, among which the one made by the American Academy of Pediatrics in 2005 recently updated (2020), the Japanese guide (2020), the first European Consensus (2021) and the International Consensus on the diagnosis, approach multidisciplinary approach and management of individuals with achondroplasia throughout life (2021). However, and despite these recommendations, there is currently a great worldwide variability in the management of people with achondroplasia, with medical, functional and psychosocial consequences in patients and their families. Therefore, it is essential to integrate these recommendations into daily clinical practice, taking into account the particular situation of each health system.

[Referral criteria to clinical genetics from primary care: Consensus document]. / Criterios de derivación a genética clínica desde Atención Primaria. Documento de consenso.

INTRODUCTION: Primary care (PC) is the first contact between the patient and the doctor, so it is essential to be clear about the criteria for suspecting a genetic disease and where it should be referred for study. MATERIAL AND METHODS: Four scientific societies: the Spanish Society of Family and Community Medicine (semFYC), the Spanish Association of Human Genetics (AEGH), the Spanish Association of Pediatrics (AEP) and the Spanish Society of Medical Oncology (SEOM), have reviewed the criteria for referral to the clinical genetics services of the different published guidelines with the purpose of define the recommendations for PC. CONCLUSIONS: With this consensus document, the PC doctor and pediatrician will know when, how and where to refer their patients with hereditary and/or genetic pathology to clinical genetics services.

Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6.

While inherited hemizygous variants in PHF6 cause X-linked recessive Borjeson-Forssman-Lehmann syndrome (BFLS) in males, de novo heterozygous variants in females are associated with an overlapping but distinct phenotype, including moderate to severe intellectual disability, characteristic facial dysmorphism, dental, finger and toe anomalies, and linear skin pigmentation. By personal communication with colleagues, we assembled 11 additional females with BFLS due to variants in PHF6. We confirm the distinct phenotype to include variable intellectual disability, recognizable facial dysmorphism and other anomalies. We observed skewed X-inactivation in blood and streaky skin pigmentation compatible with functional mosaicism. Variants occurred de novo in 10 individuals, of whom one was only mildly affected and transmitted it to her more severely affected daughter. The mutational spectrum comprises a two-exon deletion, five truncating, one splice-site and three missense variants, the latter all located in the PHD2 domain and predicted to severely destabilize the domain structure. This observation supports the hypothesis of more severe variants in females contributing to gender-specific phenotypes in addition to or in combination with effects of X-inactivation and functional mosaicism. Therefore, our findings further delineate the clinical and mutational spectrum of female BFLS and provide further insights into possible genotype-phenotype correlations between females and males.

Mowat-Wilson syndrome: growth charts.

BACKGROUND: Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. RESULTS: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. CONCLUSIONS: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum.

BACKGROUND: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement. RESULTS: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient's lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation. CONCLUSIONS: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.

Mixed Phenotype of Langer-Giedion's and Cornelia de Lange's Syndromes in an 8q23.3-q24.1 Microdeletion without TRPS1 Deletion.

Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the TRPS1 and EXT1 genes. Cornelia de Lange's syndrome (CdLS) is a genetically heterogeneous dysmorphic syndrome where heterozygous mutations of RAD21 gene have been associated with a mild clinical presentation (CDLS type 4; MIM: 614701). We report a female patient with a 2.3-Mb interstitial deletion at 8q23.3-q24.1 encompassing EXT1 and RAD21 genes but not TRPS1 . Clinical findings in this patient are correlated with a mixed phenotype of LGS and CdLS type 4.

Oxigenoterapia de alto flujo con cánula nasal en el tratamiento de la bronquiolitis aguda en neonatos / High flow nasal cannula oxygen therapy in the treatment of acute bronchiolitis in neonates

OBJETIVO: Determinar si el uso de oxigenoterapia de alto flujo (OAF) en cánulas nasales disminuye la necesidad de ventilación mecánica en neonatos hospitalizados con bronquiolitis aguda. MÉTODOS: Estudio de cohortes ambispectivo, realizado en una unidad neonatal IIB, que incluyó neonatos ingresados con bronquiolitis desde la instauración de la técnica de OAF (período-OAF: octubre de 2011-abril de 2015), comparándolo con una cohorte histórica de la temporada previa a su uso (período pre-OAF: enero de 2008-mayo de 2011). Se analizó la proporción de ventilación mecánica antes y después del inicio del tratamiento con OAF y se evaluaron parámetros clínicos y complicaciones de los pacientes tratados con esta técnica. RESULTADOS: Se incluyeron 112 neonatos, 56 del período-OAF y 56 de la temporada pre-OAF. En el período-OAF ningún paciente requirió intubación en comparación con la temporada previa, donde el 3,6% precisó ventilación mecánica invasiva. El uso de OAF se asoció con una disminución significativa de ventilación mecánica no invasiva (30,4% vs 10,7%; p = 0,01), con un RR de 0,353 (IC 95%: 0,150-0,829), RAR de 19,6% (IC 95%: 5,13-34,2) y NNT de 5. En el período-OAF 22 pacientes recibieron terapia de alto flujo y 22,7% de ellos (IC 95%: 7,8-45,4) requirieron ventilación no invasiva. Tras el inicio de OAF se observó una mejoría rápida y progresiva de la frecuencia cardiaca (p = 0,03), frecuencia respiratoria (p = 0,01) y escala clínica (p = 0,00) a partir de 3 h. No se registraron efectos adversos. CONCLUSIONES: El uso de OAF disminuye la necesidad de ventilación no invasiva y es un tratamiento seguro que consigue mejoría clínica de neonatos con bronquiolitis

OBJECTIVE: To determine whether the availability of heated humidified high-flow nasal cannula (HFNC) therapy was associated with a decrease in need for mechanical ventilation in neonates hospitalised with acute bronchiolitis. METHODS: A combined retrospective and prospective (ambispective) cohort study was performed in a type II-B Neonatal Unit, including hospitalised neonates with acute bronchiolitis after the introduction of HFNC (HFNC-period; October 2011-April 2015). They were compared with a historical cohort prior to the availability of this technique (pre-HFNC; January 2008-May 2011). The need for mechanical ventilation between the two study groups was analysed. Clinical parameters and technique-related complications were evaluated in neonates treated with HFNC. RESULTS: A total of 112 neonates were included, 56 after the introduction of HFNC and 56 from the period before the introduction of HFNC. None of patients in the HFNC-period required intubation, compared with 3.6% of the patients in the pre-HFNC group. The availability of HFNC resulted in a significant decrease in the need for non-invasive mechanical ventilation (30.4% vs 10.7%; P = .01), with a relative risk (RR) of .353 (95% CI; .150-.829), an absolute risk reduction (ARR) of 19.6% (95% CI; 5.13 - 34.2), yielding a NNT of 5. In the HFNC-period, 22 patients received high flow therapy, and 22.7% (95% CI; 7.8 to 45.4) required non-invasive ventilation. Treatment with HFNC was associated with a significant decrease in heart rate (P = .03), respiratory rate (P = .01), and an improvement in the Wood-Downes Férres score (P = .00). No adverse effects were observed. CONCLUSIONS: The availability of HFNC reduces the need for non-invasive mechanical ventilation, allowing a safe and effective medical management of neonates with acute bronchiolitis

Mycophenolate mofetil embryopathy: A newly recognized teratogenic syndrome.

Mycophenolate mofetil (MMF) is probably the most common employed immunosuppressant drug in recipients of solid organ transplant and in many autoimmune diseases. In vitro studies, a significant number of single clinical observations and a recent study from a group of different European teratogen information services, have provided very consistent data supporting the existence of a specific MMF embryopathy. The typical malformative pattern of MMF embryopathy includes external ear anomalies ranging from hypoplastic pinna (microtia) to complete absence of pinna (anotia); cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia. Other less frequent features are congenital heart defects, distal limbs anomalies, esophageal atresia, vertebral malformations, diaphragmatic hernia, and kidney and central nervous system anomalies. Neurodevelopmental outcome seems favorable in the small number of patients where information about this issue is available, but neurological deficits have been documented. Physicians in charge of women under MMF therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least six weeks before becoming pregnant.

[High flow nasal cannula oxygen therapy in the treatment of acute bronchiolitis in neonates]. / Oxigenoterapia de alto flujo con cánula nasal en el tratamiento de la bronquiolitis aguda en neonatos.

OBJECTIVE: To determine whether the availability of heated humidified high-flow nasal cannula (HFNC) therapy was associated with a decrease in need for mechanical ventilation in neonates hospitalised with acute bronchiolitis. METHODS: A combined retrospective and prospective (ambispective) cohort study was performed in a type II-B Neonatal Unit, including hospitalised neonates with acute bronchiolitis after the introduction of HFNC (HFNC-period; October 2011-April 2015). They were compared with a historical cohort prior to the availability of this technique (pre-HFNC; January 2008-May 2011). The need for mechanical ventilation between the two study groups was analysed. Clinical parameters and technique-related complications were evaluated in neonates treated with HFNC. RESULTS: A total of 112 neonates were included, 56 after the introduction of HFNC and 56 from the period before the introduction of HFNC. None of patients in the HFNC-period required intubation, compared with 3.6% of the patients in the pre-HFNC group. The availability of HFNC resulted in a significant decrease in the need for non-invasive mechanical ventilation (30.4% vs 10.7%; P=.01), with a relative risk (RR) of .353 (95% CI; .150-.829), an absolute risk reduction (ARR) of 19.6% (95% CI; 5.13 - 34.2), yielding a NNT of 5. In the HFNC-period, 22 patients received high flow therapy, and 22.7% (95% CI; 7.8 to 45.4) required non-invasive ventilation. Treatment with HFNC was associated with a significant decrease in heart rate (P=.03), respiratory rate (P=.01), and an improvement in the Wood-Downes Férres score (P=.00). No adverse effects were observed. CONCLUSIONS: The availability of HFNC reduces the need for non-invasive mechanical ventilation, allowing a safe and effective medical management of neonates with acute bronchiolitis.

Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes.

BACKGROUND: Only 15 point mutations in NFIX gene have been reported so far, nine of them cause the Marshall-Smith syndrome (MSS) and the remaining mutations lead to an overgrowth disorder with a less severe phenotype, defined as Sotos-like. METHODS: The clinical findings in three patients with MSS and two patients with a Sotos-like phenotype are presented. Analysis of the NFIX gene was performed both by conventional or next-generation sequencing. RESULTS: Five de novo mutations in NFIX gene were identified, four of them not previously reported. Two frameshift mutations and a donor-splice one caused MSS, while two missense mutations in the DNA binding/dimerisation domain entailed an overgrowth syndrome with some clinical features resembling Sotos syndrome, accompanied by a marfanoid habitus, very low BMI, long narrow face, or arachnodactyly. CONCLUSION: Marshall-Smith mutations are scattered through exons 6-10 of NFIX gene, while most point mutations causing an overgrowth syndrome are clustered in exon 2. Clinical features of this overgrowth syndrome may well be considered an intermediate phenotype between Sotos and Marfan syndromes.

Postnatal development of fetuses with a single umbilical artery: differences between malformed and non-malformed infants.

BACKGROUND: The presence of a single umbilical artery (SUA) is a fetal soft marker of congenital abnormalities. Among the most common related malformations, there are cardiological, nephrourological and digestive anomalies, most of which are considered to have a vascular etiology. There is an association between increased incidence of intrauterine growth retardation and adverse perinatal indicators, but whether this association is due to related anomalies or isolated SUA (iSUA) is controvisal. METHODS: We reviewed 96 cases of iSUA and non-isolated SUA (niSUA), diagnosed in a period of two years in a referral hospital for high-risk pregnancies. Data on prenatal explorations, including fetal ultrasonography and karyotyping, were obtained. niSUA was diagnosed when no malformations were found prenatally or in postnatal evaluation. RESULTS: Sixty-six newborns (68.8%) had no other anomalies and 30 (31.3%) presented with a variety of malformations including heart diseases, urophaties, digestive, nervous and musculoskeletal disorders, genetic abnormalities and complex malformations. Cardiological and nephrourological abnormalities were found to be the most frequent association with a SUA (both in 23.8% of malformed SUA newborns). Intrauterine growth restriction was not higher in iSUA newborns than in a normal population. Ultrasound allowed optimal prenatal diagnosis in most cases. CONCLUSIONS: The prognosis of the fetus with a SUA is determined by the presence of other malformations observed by an expert sonographer. If no other findings are made, only a routine physical examination should be performed in newborns, but no other complementary examinations are required.