Achondroplasia in Latin America: practical recommendations for the multidisciplinary care of pediatric patients.

BACKGROUND: Achondroplasia is the most common bone dysplasia associated with disproportionate short stature, and other comorbidities, such as foramen magnum stenosis, thoracolumbar kyphosis, lumbar hyperlordosis, genu varum and spinal compression. Additionally, patients affected with this condition have higher frequency of sleep disorders, ear infections, hearing loss and slowed development milestones. Considering these clinical features, we aimed to summarize the regional experts' recommendations for the multidisciplinary management of patients with achondroplasia in Latin America, a vast geographic territory with multicultural characteristics and with socio-economical differences of developing countries. METHODS: Latin American experts (from Argentina, Brazil, Chile and Colombia) particiáted of an Advisory Board meeting (October 2019), and had a structured discussion how patients with achondroplasia are followed in their healthcare centers and punctuated gaps and opportunities for regional improvement in the management of achondroplasia. RESULTS: Practical recommendations have been established for genetic counselling, prenatal diagnosis and planning of delivery in patients with achondroplasia. An outline of strategies was added as follow-up guidelines to specialists according to patient developmental phases, amongst them neurologic, orthopedic, otorhinolaryngologic, nutritional and anthropometric aspects, and related to development milestones. Additionally, the role of physical therapy, physical activity, phonoaudiology and other care related to the quality of life of patients and their families were discussed. Preoperative recommendations to patients with achondroplasia were also included. CONCLUSIONS: This study summarized the main expert recommendations for the health care professionals management of achondroplasia in Latin America, reinforcing that achondroplasia-associated comorbidities are not limited to orthopedic concerns.

International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia.

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life.

Hereditary hypophosphatemic rickets and craniosynostosis.

BACKGROUND: Craniosynostosis is an underdiagnosed complication associated with hypophosphatemic rickets. The study aims to describe the clinical and auxological characteristic of children with hypophosphatemic rickets and craniosynostosis, describe the usual treatment, and compare the characteristics with those of children without craniosynostosis. METHODS AND PATIENTS: An observational and retrospective cohort study was conducted. Clinical notes and cranial images were reviewed. Out of 96 children, only the 50 patients who had skull images were included. RESULTS: Out of 50 patients, 26 (15 males) had craniosynostosis (52%). No differences were observed in birth size, age, height, body proportions, alkaline phosphatase, serum phosphate, or percent tubular reabsorption of phosphate at first appointment among children with or without craniosynostosis. Among patients with craniosynostosis, dolichocephaly was prevalent. The sagittal suture was affected in all patients with craniosynostosis, with 19 of 26 children (73%) affected with isolated scaphocephaly. Pan-sutural craniosynostosis was present in 7 children (27%). None of the children had microcephaly, 7 of them presented macrocephaly and, in the remaining subjects, head circumference was normal. Five patients had undergone at least 1 cranial remodeling surgery. One patient with craniosynostosis was diagnosed with a Chiari I malformation. Molecular characterization of PHEX gene was performed in 14 cases. CONCLUSIONS: Craniosynostosis is an underdiagnosed complication of hypophosphatemic rickets. Many patients with normal head size and growth may go undiagnosed, thus it is important to consider this association for early diagnosis and possible surgical treatment. A multidisciplinary approach is necessary for a correct long-term follow-up.

Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants.

More than two decades since the first clinical and radiological description of odontochondroplasia (ODCD) was reported, biallelic loss of function variants in the Thyroid hormone receptor interactor 11 gene (TRIP11) were identified, the same gene implicated in the lethal disorder achondrogenesis (ACG1A). Here we report the clinical and radiological follow-up of four ODCD patients, including two siblings and an adult who interestingly has the mildest form observed to date. Four TRIP11 variants were detected, two previously unreported. Subsequently, we review the clinical and radiological findings of the 14 reported ODCD patients. The majority of ODCD patients are compound heterozygotes for TRIP11 variants, 12/14 have a null allele and a splice variant whilst one is homozygous for an in-frame splicing variant, with the splice variants resulting in residual GMAP activity and hypothesized to explain why they have ODCD and not ACG1A. However, adult patient 4 has two potentially null alleles and it remains unknown why she has very mild clinical features. The c.586C>T; p.(Gln196*) variant, previously shown by mRNA studies to result in p.Val105_Gln196del, is the most frequent variant, present in seven individuals from four families, three from different regions of the world, suggesting that it may be a variant hotspot. Another variant, c.2993_2994del; p.(Lys998Serfs*5), has been observed in two individuals with a possible common ancestor. In summary, although there are clinical and radiological characteristics common to all individuals, we demonstrate that the clinical spectrum of TRIP11-associated dysplasias is even more diverse than previously described and that common genetic variants may exist.

Growth in achondroplasia, from birth to adulthood, analysed by the JPA-2 model.

OBJECTIVES: In general population, there are three phases in the human growth curve: infancy, childhood and puberty, with different main factors involved in their regulation and mathematical models to fit them. Achondroplasia children experience a fast decreasing growth during infancy and an "adolescent growth spurt"; however, there are no longitudinal studies that cover the analysis of the whole post-natal growth. Here we analyse the whole growth curve from infancy to adulthood applying the JPA-2 mathematical model. METHODS: Twenty-seven patients, 17 girls and 10 boys with achondroplasia, who reached adult size, were included. Height growth data was collected from birth until adulthood. Individual growth curves were estimated by fitting the JPA-2 model to each individual's height for age data. RESULTS: Height growth velocity curves show that after a period of fast decreasing growth velocity since birth, with a mean of 9.7 cm/year at 1 year old, the growth velocity is stable in late preschool years, with a mean of 4.2 cm/year. In boys, age and peak height velocity in puberty were 13.75 years and 5.08 cm/year and reach a mean adult height of 130.52 cm. In girls, the age and peak height velocity in puberty were 11.1 years and 4.32 cm/year and reach a mean adult height of 119.2 cm. CONCLUSIONS: The study of individual growth curves in achondroplasia children by the JPA-2 model shows the three periods, infancy, childhood and puberty, with a similar shape but lesser in magnitude than general population.

Skeletal dysplasias in Latin America.

Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br, created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow-up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health-care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.

Recomendaciones para la evaluación del tamaño al nacer y del crecimiento posnatal de los recién nacidos prematuros / Recommendations for the assessment of birth size and postnatal growth of preterm newborns

Es innegable la necesidad de contar con curvas estándar de tamaño al nacer y crecimiento para evaluar y contribuir a orientar las acciones en la atención del neonato. Durante muchos años, se utilizaron las referencias de Lejarraga y Fustiñana, que fueron progresivamente reemplazadas por las de Fenton y Kim.Recientemente, el proyecto INTERGROWTH-21st construyó estándares de crecimiento prescriptivo para evaluar el tamaño al nacer desde las 33 semanas de edad gestacional, referencias para evaluar el tamaño al nacer desde las 24 a las 32,6 semanas de edad gestacional y curvas para el seguimiento longitudinal del crecimiento de recién nacidos pretérmino desde las 27 semanas de edad gestacional. Los Comités de Crecimiento y Desarrollo y de Estudios Feto-neonatales de la Sociedad Argentina de Pediatría, en conjunto con la Secretaría de Gobierno de Salud de la Nación, acordaron recomendar el reemplazo de las curvas de Fenton y Kim por las de INTERGROWTH-21st

It is unquestionable the need to have standards of size at birth and growth to evaluate and contribute to guide the actions in the care of the newborn. For many years the references of Lejarraga and Fustiñana were used, progressively replaced by those of Fenton and Kim. However, recently, the INTERGROWTH-21st project has developed prescriptive growth standards to evaluate the size at birth from 33 weeks of gestational age, references from 24 to 32.6 weeks of gestational age, and curves for postnatal growth from 27 weeks of gestational age onward. The Growth and Development and Neonatal Fetal Studies Committees of the Argentine Society of Pediatrics in conjunction with the Secretary of National Government of Health agreed to recommend the replacement of the Fenton and Kim curves with those of INTERGROWTH-21st.

[Recommendations for the assessment of birth size and postnatal growth of preterm newborns]. / Recomendaciones para la evaluación del tamaño al nacer y del crecimiento posnatal de los recién nacidos prematuros.

It is unquestionable the need to have standards of size at birth and growth to evaluate and contribute to guide the actions in the care of the newborn. For many years the references of Lejarraga and Fustiñana were used, progressively replaced by those of Fenton and Kim. However, recently, the INTERGROWTH-21st project has developed prescriptive growth standards to evaluate the size at birth from 33 weeks of gestational age, references from 24 to 32.6 weeks of gestational age, and curves for postnatal growth from 27 weeks of gestational age onward. The Growth and Development and Neonatal Fetal Studies Committees of the Argentine Society of Pediatrics in conjunction with the Secretary of National Government of Health agreed to recommend the replacement of the Fenton and Kim curves with those of INTERGROWTH-21st.

Es innegable la necesidad de contar con curvas estándar de tamaño al nacer y crecimiento para evaluar y contribuir a orientar las acciones en la atención del neonato. Durante muchos años, se utilizaron las referencias de Lejarraga y Fustiñana, que fueron progresivamente reemplazadas por las de Fenton y Kim. Recientemente, el proyecto INTERGROWTH-21st construyó estándares de crecimiento prescriptivo para evaluar el tamaño al nacer desde las 33 semanas de edad gestacional, referencias para evaluar el tamaño al nacer desde las 24 a las 32,6 semanas de edad gestacional y curvas para el seguimiento longitudinal del crecimiento de recién nacidos pretérmino desde las 27 semanas de edad gestacional. Los Comités de Crecimiento y Desarrollo y de Estudios Feto-neonatales de la Sociedad Argentina de Pediatría, en conjunto con la Secretaría de Gobierno de Salud de la Nación, acordaron recomendar el reemplazo de las curvas de Fenton y Kim por las de INTERGROWTH-21st.

Evaluation of the INTERGROWTH-21st project newborn standard for neonatal phenotypes and neonatal morbidity and mortality.

INTRODUCTION: The use of local references or standard for neonatal studies still requires their validation through indicators of morbidity and mortality. OBJECTIVE: evaluate the performance of the INTERGROWTH-21st Project (IG-21) standard and a commonly used Argentinian reference (Urquia) by examining the differences in the frequency of growth phenotypes, and the associated neonatal morbidity and mortality. METHODS: Retrospective cohort study of all singleton live-births from Sarda Maternity Hospital (Buenos Aires, Argentina) between 33 and 42 gestational age, using information obtained from a Perinatal Surveillance System (Agustina) dataset between 1996-2001 (n = 25948). Phenotypes small- and large-for-gestational age, stunting and waisting and a composite of neonatal morbidity/mortality (CNMM) were contrasted between the IG-21 standard and Urquia reference. RESULTS: the Urquia 3rd centile value was lower than IG-21 before 37 weeks, but then it surpassed IG-21 until term. Among Sarda , 2.3%, 5.9% and 8.9 were <3rd, <10th and >97th centile, respectively, under the IG-21 standard, while 3.7%, 10.1% and 8.4% were <3rd, <10th and >97th centile, respectively, under the Urquia reference. Stunting and waisting were 16.1% and 0.9%, respectively under IG-21. The IG-21 detection rates of CNMM showed that 28.5%, 19.6% and 8.5% occurred among weight<3rd,<10th and >97th centile, respectively, while 21.8%, 14.2% and 8.0%  occurred among <3rd, <10th and >97th centile under the Urquia criteria. Newborn weight <3rd,<10th and >97th  centile under IG-21 showed higher neonatal CNMM risk compared with Urquia reference. CONCLUSIONS: The IG-21 standard identified a higher risk of neonatal morbidity and mortality than the Urquia reference.

Introducción: El uso de referencias locales o estándares para estudios neonatales aún requiere su validación a través de indicadores de morbilidad y mortalidad. Objetivo: Comparar la capacidad predictiva del estándar INTERGROWTH-21st (IG-21st) y una referencia argentina (Urquia) mediante los fenotipos de crecimiento fetal y morbi-mortalidad neonatales. Métodos: Estudio de cohorte retrospectivo de recién nacidos vivos entre 33 y 42 semanas del Hospital Materno-Infantil Ramón Sarda (Buenos Aires, Argentina), entre 1996-2001 (n = 25948). Los fenotipos pequeños (PEG) y grandes para la edad gestacional, acortado y emaciado y un índice compuesto de morbilidad / mortalidad neonatal (CNMM) se contrastaron entre IG-21st y la referencia Urquia. Resultados: El 3er percentil del peso al nacer de Urquia fue menor que el de IG-21st antes de las 37 semanas; 2.3%, 5.9% y 8.9 de los RN fueron <3o, <10° y > 97° percentil, respectivamente, bajo el estándar IG-21st, mientras que 3,7%, 10,1% y 8,4% fueron <3 °, <10 ° y> 97 ° percentil, respectivamente, bajo la referencia Urquia. Acortados fueron 16.1% y emaciados 0.9%, bajo IG-21st. CNMM bajo IG-21st fueron 28.5%, 19.6% y 8.5% en peso<3o, <10º y >97º percentil, respectivamente, mientras que 21.8%, 14.2% y 8.0% ocurrieron en peso< 3°, <10° y > 97° percentil bajo Urquia. Acortados fueron 17.3% y emaciados 18.3%. Los RN <3er°, <10° y > 97° percentil bajo IG-21st mostraron mayor riesgo de CNMM en comparación con la referencia Urquia. Conclusiones: El estándar IG-21st identificó mayor riesgo de morbilidad y mortalidad que la referencia Urquia.

Clinical and Radiologic Evaluation of an Individual with Hypochondroplasia and a Novel FGFR3 Mutation.

Hypochondroplasia (HCH), a skeletal dysplasia caused by mutations in the fibroblast growth factor receptor 3 ( FGFR3 ) gene, is characterized by disproportionate short stature. The p.Asn540Lys (p.N540K) mutation accounts for ∼50 to 70% of cases of HCH, but novel FGFR3 mutations are described. We present a family with disproportionately short stature and mild radiologic findings seen in a major public pediatric hospital in Argentina. A previously undescribed heterozygous missense variant in FGFR3, NM_000142.4:667C > T; p.(Arg223Cys) was identified. The predicted phenotype correlates well with the mild auxologic and radiologic characteristics observed. In this case, disproportionately short stature raised the suspicion of skeletal dysplasia.

SHOX Deficiency in Argentinean Cohort: Long-Term Auxological Follow-Up and a Family's New Mutation.

A cohort study on the growth of 19 Argentinean children, aged 0 to 18 years, and 11 of their first-degree relatives with alterations in the SHOX gene or its regulatory regions is reported. Children are born shorter and experience a growth delay during childhood with a stunted pubertal growth spurt. Body disproportion, with a sitting height/height ratio above +2 standard deviation score (SDS), was already present as early as 2 years old. Hand length was normal. Shortening of the radius, with a length below -1.9 SDS, was the earliest and most frequent radiological sign detected as early as 45 days old. We found a previously unreported mutation in a family with a highly variable phenotype, the boy had a severe phenotype with a milder presentation in other affected members of the family. We conclude that body disproportion and a shorter radius length on X-ray are useful tools for selecting children to undergo SHOX molecular studies.

A Prospective Study on Changes in Nutritional Status and Growth Following Two Years of Ketogenic Diet (KD) Therapy in Children with Refractory Epilepsy.

INTRODUCTION: Epilepsy is a neurological disorder characterized by an increased susceptibility to seizures. The ketogenic diet (KD) is currently the most important alternative non-pharmacological treatment. Despite its long history of clinical use, it is not clear how this diet affects longitudinal growth in children. METHODS: A prospective study was designed to evaluate growth and nutritional status in 45 children on KD. Growth was assessed by measuring weight, height, and body mass index (BMI). Standard deviation scores (SDS) were calculated for all measurement parameters at KD initiation and at a two-year follow-up. RESULTS: Overall, 45 patients who completed 24 months on KD were enrolled. Median age was 6.6 years (0.8 to 17.3), with a male predominance (n = 23); 74% of the 45 patients were responders on seizure reduction at three months; 26% of patients were non-responders. In our study, using -1 SDS as a cut-off point, growth deceleration was observed in 9% (n: 4) of the patients; however, the nutritional status was maintained or even improved. No correlation with age, sex, or ambulatory status was found. CONCLUSIONS: The nutritional follow-up of these patients was helpful to improve overweight and thinness but could not avoid growth deceleration in some of them. These findings confirm that children with refractory epilepsy on KD treatment require careful growth monitoring.

Height growth velocity during infancy and childhood in achondroplasia.

There is a lack of knowledge about longitudinal growth during childhood in achondroplasia. We report patterns of linear growth and height growth velocity references. The sample consisted of 84 children, 41 girls and 43 boys. Growth data was collected from birth until mid-childhood. The median (interquartile range) number of measurements per child was 13.5 (12, 15). Individual growth curves were estimated by fitting the Reed 1st model to each individual's height for age data. Height growth velocities references for age centiles were calculated by LMS method. Mean (SD) birth length was 46.14 cm (2.17) and 45.53 cm (2.16), for boys and girls respectively. Individual growth curves were analyzed. Shifts in growth channels were seen: out of 84 infants, 41 (48.8%) changed more than 1 SDS between birth to 5 years old. The numbers of infants shifting upward were similar (20/84) to the infants shifting downward (21/84). Height growth velocity curves show that after a period of fast decreasing growth velocity since birth, with a mean of 15.5 cm/year and 9.5 cm/year at 6 month and 1 year old, the growth velocity is stable in late preschool years, with a mean of 4.3 cm/year. Shifts in growth channels were seen between birth and 5 years old. Professionals who follow up them must consider this phenomenon during infancy. ACH children experienced a period of fast decreasing growth during infancy and the growth curve was similar in shape and lesser in magnitude than the general population.

FGFR3-related hypochondroplasia: longitudinal growth in 57 children with the p.Asn540Lys mutation.

Background Children with hypochondroplasia (HCH), who have FGFR3 mutations c.1620C>A or c.1620C>G (p.Asn540Lys) appear to have a more severe phenotype than those with HCH without these mutations. We describe the change in height, leg length and body proportions in a retrospective cohort of children with HCH related-p.Asn540Lys mutation and we compared them with Argentine population. Methods Anthropometric measurements were initially taken and followed up by the same observer, with standardized techniques. Sitting height/height and head circumference/height ratio were calculated as a body disproportion indicator. In order to make a comparison with the Argentine population height average, centiles of height, leg length and body proportions were estimated by the LMS method. Results The sample consisted of 57 HCH children (29 males and 28 females) between the ages of 0-18 years. The median (interquartile range) number of measurements per child was 8 (4.3, 13) for height, 7 (4, 12) for sitting height and 7.5 (4, 12.8) for head circumference. Leg length increased from 17 cm at birth to approximately 54 cm in adolescents, 25 cm shorter than the leg length in non-HCH populations. Sitting height increased from 39 cm at birth to 81 cm in adolescents, 7 cm below mean in non-HCH adolescents. Mean (range) adult height were 143.6 cm (131-154.5) and 130.8 cm (124-138) for males and females, respectively. Conclusions The disharmonic growth between the less affected trunk and the severely affected limbs determine body disproportion in HCH.

Growth velocity and biological variables during puberty in achondroplasia.

BACKGROUND: Achondroplasia is the most common form of inherited disproportionate short stature. Cross-sectional design studies of height show that, during childhood, height standard deviation scores (SDS) declines steadily and reaches a mean adult height at -6.42 and -6.72 SDS. However, there is a lack of knowledge about longitudinal growth and biological variables during puberty for children with achondroplasia. Here we report the growth velocity and biological parameters during puberty in children with achondroplasia. METHODS: The study was an observational, cohort study. A total of 23 patients, 15 girls and eight boys with achondroplasia, who reached adult size were included. Growth data was collected from mid-childhood until final height by the same trained observer. Individual growth curves were estimated by fitting the Preece-Baines model 1 (PB1) to each individual's height for age data. Pubertal development was scored on Tanner scale on each visit. RESULTS: In boys with achondroplasia the mean adult height was 129.18 cm. Age and velocity at peak velocity in puberty were 13.89 years and 4.86 cm/year, respectively. The adolescent gain was 20.40 cm. Mean age at genital development 2 and 5 were 12.16 (0.60) and 14.97 (0.88), respectively. In girls the mean adult height was 118.67 cm. Age and velocity at peak velocity in puberty were 11.45 years and 4.40 cm/year, respectively. The adolescent gain was 19.35 cm. Mean age at breast 2 and 4 were 10.20 (1.24) and 12.49 (1.07), respectively. CONCLUSIONS: Children with achondroplasia experienced an adolescent growth spurt, which was similar in shape and half the magnitude of the non-achondroplasia population.

Leg length, sitting height, and body proportions references for achondroplasia: New tools for monitoring growth.

Achondroplasia is the most common form of inherited disproportionate short stature. We report leg length, sitting height, and body proportion curves for achondroplasia. Seven centile format of sitting height, leg length, sitting height/leg length ratio, sitting height/height ratio, and head circumference/height ratio were estimated by the LMS method. The Q-test was applied to assess the goodness of fit. For comparison, centiles of sitting height and leg length were graphed using Argentine national growth references for achondroplasia and non-achondroplasia populations. The sample consisted of 342 children with achondroplasia (171 males, 171 females) aged 0-18 years. The median (interquartile range) number of measurements per child was 6 (3, 12) for sitting height and 8 (3, 13) for head circumference. Median leg length increased from 14 cm at age 1 week to 44 and 40 cm (males and females, respectively) in achondroplasia adolescents which is 3.5 cm shorter than non-achondroplasia children at age 1 week and, 38 cm shorter at adolescence. Median sitting height increased from 34 cm at birth to 86 and 81 in adolescents' boys and girls respectively, only 5 cm shorter than non-achondroplasia children. Sitting height/leg length decreased from 2.61 at birth to approximately 1.90 at adolescent. Median head circumference/height ratio decreased from 0.79 at birth to 0.46 at 18 years in both sexes. Growth of lower limbs is affected early in life and becomes more noticeable throughout childhood. The disharmonic growth between the less affected trunk and the severely affected limbs determine body disproportion in achondroplasia.