An intermediate phenotype in IDH related enchondromatosis spectrum.

Mosaic variants of IDH1 (isocitrate dehydrogenase-1) R132 and IDH2 (isocitrate dehydrogenase-2) R172 loci were detected in most of the bone cysts of Ollier and Maffucci series and in the blood and tissue samples of metaphyseal enchondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) patients. We aimed to report an intermediate phenotype comparing with the reported cases. The proband was a 9-year-old boy with widespread metaphyseal enchondromatosis involving metaphyses of long tubular bones, iliac bones and tubular bones of both hands and feet and sparing spine and flat and short bones. He underwent quad whole exome sequencing (index-both parents-healthy sibling). Sanger sequencing was performed for confirmation and segregation purposes. Heterozygous IDH1 R132H (c.395G > A) variant was detected in his blood via whole exome sequencing and Sanger analysis in mosaic state, 22% of the reads and Sanger signal. He had no D-2-hydroxyglutaric aciduria in urinary organic acid analysis. Our case is unique with the presence of IDH1 R132H variant in blood with metaphyseal enchondromatosis without D-2-hydroxyglutaric aciduria. It was a transitional phenotype. With his phenotype, we expand the IDH1/IDH2 related enchondromatosis phenotypes.

Síndrome 3-M: descripción clínica-radiológica: caso clínico / 3-M syndrome: clinical and radiological description. Case report

Introducción: El síndrome 3M combina retardo de crecimiento prenatal y postnatal severo, dismorfias faciales (semeja facies "melancólica") y anomalías radiológicas. Es una enfermedad infrecuente de la que hasta el momento se han descrito alrededor de 200 casos. "3M" se refiere a las iniciales de los tres autores que describieron este síndrome. Los rasgos faciales característicos son: cabeza relativamente grande, dolicocefalia, abombamiento frontal, cara triangular, mentón prominente, nariz antevertida, labios gruesos, cejas gruesas, surco nasolabial largo e hipoplasia de tercio medio de cara. Los hallazgos radiológicos, que van apareciendo con la edad son costillas y huesos largos finos y delgados, y cuerpos vertebrales altos. El síndrome 3M se transmite como un rasgo autosómico recesivo y es genéticamente heterogéneo. Objetivo: Descripción del caso clínico de una nina actualmente de 10 años de edad en el que se confirmó este síndrome. Caso clínico: Nina referida a Genética a los 15 meses de vida, por talla baja severa, dismorfias y malformaciones. Su seguimiento clínico y radiológico permitió plantear y confirmar este diagnóstico. Conclusión: En ocasiones sólo el seguimiento longitudinal de pacientes con talla baja severa permite que se evidencien alteraciones sugerentes de un diagnóstico específico. La certificación del diagnóstico favorece un adecuado manejo clínico y consejería genética a los padres.

Introduction: 3M syndrome combines severe prenatal and postnatal growth delay, facial dysmorphism (resembles melancholy facies) and radiological abnormalities. It is a rare disease with 200 cases reported so far. "3M" refers to the initials of the three authors who first described this syndrome. The characteristic facial features are: relatively large head, dolichocephaly, frontal bossing, a triangular face, pointed chin, upturned nose, full lips, full eyebrows, long philtrum and hypoplastic midface. radiological findings which appear with age, include slender long bones and ribs and tall vertebral bodies. 3M syndrome is transmitted as an autosomal recessive trait and is genetically heterogeneous. Objective: Report the clinical case of a girl, now 10 years of age, diagnosed with the syndrome. Case report: An infant girl, 15 months old, was referred to Genetics Clinic due to severe short stature, dysmorphic features and malformations. Her clinical and radiological follow-up led to propose and confirm this diagnosis. Conclusion: Sometimes only longitudinal monitoring of patients with severe short stature evidence abnormalities suggesting a specific diagnosis. The right diagnosis results in suitable clinical care and genetic counseling to parents.

Genotypes and phenotypes of children with SHOX deficiency in France.

CONTEXT: The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified. OBJECTIVES: The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France. DESIGN, SETTING, AND PATIENTS: Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS). INTERVENTION AND MAIN OUTCOME MEASURE: SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D). RESULTS: Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies. CONCLUSIONS: SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.