3M syndrome (Miller, McKusick, Malvaux): Another cause of genetic short stature

Abstract

Background: Linear growth during childhood is a process regulated and affected by many factors involved, such as prenatal, nutritional, hormonal, environmental or genetic. Short stature has been universally defined as a child with a score of less than 2 standard deviations for his or her age and sex. On the other hand, genetic short stature is a rare condition, which should be suspected in patients with severe short stature (defined as a height below less than 3 standard deviations according to World Health Organization curves), who present disproportions in body measurements or who have associated malformations. We describe the case of a schoolgirl with clinical findings and molecular studies that led to the diagnosis of 3M Syndrome.

Purpose: To present a rare cause of short stature of genetic origin in a pediatric patient.

Case presentation: Female patient aged 9 years and 10 months, with a perinatal history of intrauterine growth restriction and with anthropometry at birth compatible with parameters of small for gestational age. On physical examination, she presented severe short stature (-4.98 SD WHO curves), phenotype with prominent forehead, triangular face, borderline and rotated ears, bulbous nose and thick lips, with a pointed chin and narrow thorax. Her IQ and karyotype were normal. An individual whole exome sequencing was performed which reported a homozygous pathogenic variant in the CUL7 gene c.2398-2A>G, confirming the diagnosis of 3M Syndrome.

Discussion and conclusion: The etiological diagnosis of genetic short stature is challenging, and clinical and biochemical data may not be sufficient, requiring the use of new generation molecular tests that allow in some cases to find the etiology, guide the treatment and know the prognosis. In this patient, the clinical exome study allowed the diagnosis of 3M Syndrome and guided the intervention, avoiding economic expenses, prolonged treatments and false expectations about the use of growth hormone, which may not have an adequate response in this condition.

3M syndrome should be considered within the differential diagnosis of short stature, especially when the patient has normal cognitive performance. Molecular analysis of the CUL7, OBSL1 and CCDC8 genes is necessary to confirm the clinical diagnosis in suspected cases and to provide appropriate genetic counseling and treatment.