Clinical characteristics: Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with three M syndrome have hypogonadism and occasionally hypospadias.
Diagnosis/testing: The diagnosis of three M syndrome is established in a proband with characteristic clinical and radiographic features. Identification of biallelic pathogenic variants in CCDC8, CUL7, or OBSL1 can establish the diagnosis if clinical and radiographic features are inconclusive.
Management: Treatment of manifestations: Surgical bone lengthening may be an option. Adaptive aids for people with short stature are appropriate. Significant joint laxity should prompt orthopedic evaluation and measures to control the development of arthritis. Males with three M syndrome should be referred for endocrinologic evaluation regarding gonadal function at puberty.
Surveillance: Monitoring of growth every 6-12 months on standard growth charts, with special attention to growth velocity.
Genetic counseling: Three M syndrome is inherited in an autosomal recessive manner. Each sib of a proband with three M syndrome has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the pathogenic variants have been identified in an affected family member. Prenatal ultrasound examination reveals slowing of growth of all long bones.
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