Pathogenic variants in the TRIP11 gene cause a skeletal dysplasia spectrum from odontochondrodysplasia to achondrogenesis 1A.

The thyroid hormone receptor interactor 11 (TRIP11) gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), a protein essential for the operation of the Golgi apparatus. It is known that null mutations in TRIP11 disrupt Golgi function and cause a lethal skeletal dysplasia known as achondrogenesis type 1A (ACG1A), however recently, hypomorphic mutations in that gene have been linked to odontochondrodysplasia (ODCD), a nonlethal skeletal dysplasia characterized by skeletal changes in the spine and in the metaphyseal regions, associated with dentinogenesis imperfecta. Here we present two patients reflecting the phenotypic spectrum related to different TRIP11 variants. The first is a female child with ODCD, for whom a homozygous in-frame splicing mutation in intron 9 of TRIP11 was identified. The mutation appears to lead to the expression of an alternative TRIP11 transcript, that may explain the less severe radiological alterations in ODCD. The second is a fetus with classical form of ACG1A, associated with typical molecular findings (frameshift) in exon 11 of TRIP11, both novel mutations. The two patients reported here represent the TRIP11 spectrum of skeletal dysplasia ranging from mild to lethal phenotypes, thereby enabling one to suggest a genotype-phenotype correlation in these diseases.

Hematoma de Morel Lavallée gigante en la rodilla derecha: reporte de un caso / Giant Morel Lavallée hematoma in the right knee: case report

RESUMEN Se presenta el caso del paciente de 36 años de edad, con antecedentes de acondroplasia que desde hace 7 meses sufrió una lesión traumática no de gravedad en la rodilla derecha. La cual comienza a aumentar de volumen con contenido líquido fluctuante. Fue puncionado en dos ocasiones obteniéndose líquido serohemático; al no resolver y continuar aumentando de tamaño, se le plantea que es portador de un hematoma seroso de Morel Lavallée, que se produce por la fricción entre el tejido celular subcutáneo y la fascia. Su localización es infrecuente en la rodilla por lo que se decide presentar el caso ya que en la literatura revisada; no aparece ningún caso descrito. Por lo que constituye el objetivo principal de este trabajo, describir su proceder y la eficacia del tratamiento quirúrgico, con el que se obtuvo resultado satisfactorio (AU).

ABSTRACT We present the case of a patient aged 36 years, with antecedents of achondroplasia who 7 months ago suffered a non serious traumatic lesion in the right knee. The volume of the lesion began to increase with a fluctuant fluid contain. It was punctured twice draining serohematic fluid; it did not solve and the size increased more and more, so the patient was said that he had a serous Morel Lavallée hematoma, produced by the friction between the subcutaneous cell tissue and fascia. Its location in the knee is infrequent and it was not found any case like this in the reviewed literature; therefore we decided to present the case. The main objective of our work was describing it, showing the procedure and efficacy of the surgical that gave a satisfactory result (AU).

Hematoma de Morel Lavallée gigante en la rodilla derecha: reporte de un caso / Giant Morel Lavallée hematoma in the right knee: case report

RESUMEN Se presenta el caso del paciente de 36 años de edad, con antecedentes de acondroplasia que desde hace 7 meses sufrió una lesión traumática no de gravedad en la rodilla derecha. La cual comienza a aumentar de volumen con contenido líquido fluctuante. Fue puncionado en dos ocasiones obteniéndose líquido serohemático; al no resolver y continuar aumentando de tamaño, se le plantea que es portador de un hematoma seroso de Morel Lavallée, que se produce por la fricción entre el tejido celular subcutáneo y la fascia. Su localización es infrecuente en la rodilla por lo que se decide presentar el caso ya que en la literatura revisada; no aparece ningún caso descrito. Por lo que constituye el objetivo principal de este trabajo, describir su proceder y la eficacia del tratamiento quirúrgico, con el que se obtuvo resultado satisfactorio (AU).

ABSTRACT We present the case of a patient aged 36 years, with antecedents of achondroplasia who 7 months ago suffered a non serious traumatic lesion in the right knee. The volume of the lesion began to increase with a fluctuant fluid contain. It was punctured twice draining serohematic fluid; it did not solve and the size increased more and more, so the patient was said that he had a serous Morel Lavallée hematoma, produced by the friction between the subcutaneous cell tissue and fascia. Its location in the knee is infrequent and it was not found any case like this in the reviewed literature; therefore we decided to present the case. The main objective of our work was describing it, showing the procedure and efficacy of the surgical that gave a satisfactory result (AU).

Natural history of 39 patients with Achondroplasia.

OBJECTIVES: To characterize the natural history of 39 achondroplastic patients diagnosed by clinical, radiological and molecular assessments. METHODS: Observational and retrospective study of 39 patients who were attended at a public tertiary level hospital between 1995 and 2016. RESULTS: Diagnosis was made prenatally in 11 patients, at birth in 9 patients and within the first year of life in 13 patients. The most prevalent clinical findings were short stature, high forehead, trident hands, genu varum and macrocephaly. The most prevalent radiographic findings were rhizomelic shortening of the long bones and narrowing of the interpediculate distance of the caudal spine. There was motor developmental delay in 18 patients and speech delay in 16 patients. The most common clinical intercurrences were middle ear dysfunction, sleep apnea, limb pain and obesity from 2 to 9 years of age. One patient was large for the gestational age but did not develop obesity. One patient developed hydrocephalus at 10 years old. The current age of the patients varies from 15 months to 36 years. The molecular study performed by Sanger sequencing of the common heterozygous mutation 1138G>A in FGFR3 was positive in all patients. Four cases were inherited, and 35 were sporadic (paternal age from 19 to 66 years). CONCLUSIONS: The diagnoses were made early based on clinical and radiographic findings. All cases were confirmed molecularly. Despite presenting a benign course, it is necessary to establish a systematic protocol for the surveillance of these patients due to the common clinical intercurrences.

New subtype of familial achondrogenesis type IA (Houston-Harris). / Nuevo subtipo de acondrogénesis familiar tipo IA (Houston-Harris)

Background: Achondrogenesis is a skeletal dysplasia characterized primarily by short stature, severe micromelia, short and narrow chest, prematurity, polyhydramnios, fetal hydrops, and in utero or neonatal death. Based on the radiological and histopathological findings, there are three types of achondrogenesis: type 1A (Houston-Harris), type 1B (Fraccaro) and type 2 (Langer-Saldino). Clinical case: A premature female product was studied whose clinical, radiological and histopathological characteristics were compatible with achondrogenesis Type 1A. The family information allowed us to conclude that the 4 products of the 6 previous pregnancies were affected. Statistical analysis in at least 4 families previously described, including this family case showed significant differences between expected and observed number of members, being incongruent with an autosomal recessive mode of inheritance previously reported. Conclusions: therefore, it could be considered a new subtype of achondrogenesis type 1A due to the presence of a preferential germline mutation.

Introducción: La acondrogénesis es una displasia esquelética que se caracteriza principalmente por talla baja, micromelia grave, tórax corto y estrecho, prematurez, polihidramnios, hidropesía fetal y muerte fetal in utero o neonatal. Según los hallazgos radiológicos e histopatológicos existen tres tipos de acondrogénesis: tipo 1A (Houston-Harris), tipo 1B (Fraccaro) y tipo 2 (Langer-Saldino). Caso clínico: Se sometió a estudio a un producto femenino prematuro cuyas características clínicas, radiológicas e histopatológicas fueron compatibles con acondrogénesis tipo 1A. La información familiar permitió concluir que los cuatro productos de los seis embarazos previos se encontraban afectados. El análisis estadístico en por lo menos cuatro familias previamente descritas, incluyendo este caso familiar, mostró diferencias significativas entre el número de miembros esperado y el observado, siendo incongruente con el modo de herencia autosómico recesivo previamente reportado. Conclusiones: Podría considerarse un nuevo subtipo de acondrogénesis tipo 1A debida a la presencia de una mutación germinal preferencial.

Natural history of 39 patients with Achondroplasia

OBJECTIVES: To characterize the natural history of 39 achondroplastic patients diagnosed by clinical, radiological and molecular assessments. METHODS: Observational and retrospective study of 39 patients who were attended at a public tertiary level hospital between 1995 and 2016. RESULTS: Diagnosis was made prenatally in 11 patients, at birth in 9 patients and within the first year of life in 13 patients. The most prevalent clinical findings were short stature, high forehead, trident hands, genu varum and macrocephaly. The most prevalent radiographic findings were rhizomelic shortening of the long bones and narrowing of the interpediculate distance of the caudal spine. There was motor developmental delay in 18 patients and speech delay in 16 patients. The most common clinical intercurrences were middle ear dysfunction, sleep apnea, limb pain and obesity from 2 to 9 years of age. One patient was large for the gestational age but did not develop obesity. One patient developed hydrocephalus at 10 years old. The current age of the patients varies from 15 months to 36 years. The molecular study performed by Sanger sequencing of the common heterozygous mutation 1138G>A in FGFR3 was positive in all patients. Four cases were inherited, and 35 were sporadic (paternal age from 19 to 66 years). CONCLUSIONS: The diagnoses were made early based on clinical and radiographic findings. All cases were confirmed molecularly. Despite presenting a benign course, it is necessary to establish a systematic protocol for the surveillance of these patients due to the common clinical intercurrences.

A novel COMP mutation in an Inuit patient with pseudoachondroplasia and severe short stature.

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia, generally identified clinically at two years of age due to decreased linear growth and a waddling gait. Radiographic features include small and irregular epiphyses, with metaphyseal changes of the long bones and characteristic vertebral changes. Mutations in the COMP gene cause PSACH and some cases of multiple epiphyseal dysplasia. Mutations generally cluster in the calmodulin-like repeat regions of the gene. Mutations in exon 13 (encoding the seventh calmodulin-like repeat) have been associated with severe short stature (-6 SD) in PSACH. We examined an Inuit boy with PSACH and severe short stature. Height essentially remained at -1 SD on the PSACH growth curve (-7.5 SD on a normal growth curve at 10.5 years). Analysis of COMP in our patient revealed a previously undescribed heterozygous A>T substitution in exon 8, at nucleotide 812. This change in the sequence resulted in replacement of a highly conserved and negatively charged aspartic acid with an uncharged, hydrophobic valine at amino acid position 271. Both unaffected parents were negative for this genetic change. This exon encodes the first calmodulin-like repeat, which has not been previously implicated in severe short stature. We propose that this novel missense substitution is responsible for the phenotype of this patient.

Co-occurrence of achondroplasia and Down syndrome: Genotype/phenotype association.

BACKGROUND: This report describes the sixth case of an unusual association: Down syndrome with achondroplasia. It also analyzes the effects of both of these disorders on patient phenotype. METHODS: A male infant was evaluated for Down syndrome. His appearance also suggested a diagnosis of achondroplasia. The child was evaluated by physical examination, radiography, cytogenetic study, and mutation analysis. RESULTS: Chromosome analysis showed a karyotype of 47,XY,+21 in all 30 cells analyzed. Radiographic examination showed typical findings of achondroplasia, such as disproportionately large skull, shortening of limb segments, and lumbar lordosis. FGFR3 screening showed a heterozygous G1138A mutation. CONCLUSIONS: The interaction of these two distinct genetic disorders in the same patient produces a phenotype typical of each syndrome with some overlapping signs. This case represents de novo origin of two disorders that both may be parental-age related.

Sleep-related respiratory abnormalities and arousal pattern in achondroplasia during early infancy.

OBJECTIVE: To assess sleep-disordered breathing (SDB), sleep architecture, and arousal pattern in infants with achondroplasia and to evaluate the relationship between foramen magnum size and the severity of SDB. STUDY DESIGN: A retrospective review of polysomnographic recordings and medical records was performed in infants with achondroplasia and in aged-matched control subjects. All studies were re-scored with the emphasis on respiratory events, sleep state, and arousals. In addition, the neuroimaging study of the brain (magnetic resonance imaging) was reviewed to evaluate foramen magnum diameters and to assess their relationship to SDB. RESULTS: Twenty-four infants met the criteria for entry into analysis, 12 infants with achondroplasia (A) and 12 control infants (C). There was no significant difference in age or sex. Infants with achondroplasia had a significant increase in total respiratory disturbance index (RDI; A, 13.9 +/- 10.8 versus C, 2.0 +/- 0.9; P < .05). However, there was no significant difference in percentages of active sleep, quiet sleep, or sleep efficiency. Analysis of arousals demonstrated that infants with achondroplasia had a significant decrease in both spontaneous arousal index (A, 10.5 +/- 3.5/hr versus C, 18.6 +/- 2.7; P < .0001) and respiratory arousals (A, 10.3% +/- 6.3% versus C, 27.5 +/- 9.5%; P < .0001). Evaluation of foramen magnum dimensions demonstrated smaller foramen magnum size, but there were no significant correlations between anteroposterior or transverse diameters and RDI. CONCLUSION: Infants with achondroplasia have significant SDB during early infancy. SDB in infants with achondroplasia is not associated with alteration in sleep architecture, possibly because of attenuation of the arousal response. We speculate that the concomitant increased apneic events and decreased arousal response will lead to vulnerability in these infants and may underlie the pathophysiologic mechanism of sudden unexpected death in this population.

Evaluación del crecimiento en los acondroplásicos / Growth assessment in achondroplasia

Se describen dos casos clínicos de acondroplasia, atendidos en el Servicio Nutrición, Crecimiento y Desarrollo del Hospital de Niños J. M. e los Ríos, de Caracas, y se destacan sus características clínicas y antropométricas más importantes. Como se trata de una alteración del crecimiento, su evaluación y control, con los habituales valores de referencia (Tanner-Whitehouse(TW) o estudio transversal de Caracas (ETC)) para poblaciones normales, no es adecuado. Se recomienda que en la evaluación y el seguimiento del crecimiento de estos pacientes, se usen gráficas que proporcionen valores de crecimiento característicos de la población de acondroplásicos

Apnea and sudden unexpected death in infants with achondroplasia.

Thirteen infants with achondroplasia and sudden unexpected death or unexplained apnea were discovered through nonsystematic retrospective case collection. Most were initially thought to have died from sudden infant death syndrome. However, historical and pathologic findings suggest that many of these infants had apnea and sudden unexpected death secondary to acute or chronic compression of the lower brainstem or cervical spinal cord. Infants with achondroplasia evidently are at considerably increased risk for such deaths between 1 month and 1 year of age. Appropriate intervention, given these previously unrecognized risks, may include cervical restraint, polysomnographic evaluation, and apnea monitoring.

Achondroplasia and pregnancy

A pregnant achondroplastic dwarf whose mother was also dwarfed, was delivered of a live infant with achondroplastic features. To the author's knowledge, there has been no previously published report of the occurence of dwarfism in three successive generations. This is probably because of a high perinatal loss due either to a lethal homozygous gene, hydrocephaly or to respiratory failure (AU)