3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient

Abstract

3-M syndrome is a rare autosomal recessive disorder that causes short stature, unusual facial features and skeletal abnormalities. Mutations in the CUL7, OBSL1 and CCDC8 genes could be responsible for 3-M syndrome.Here we describe the growth and evolution of dismorphic features of an Italian boy with 3-M syndrome and growth hormone deficiency (GHD) from birth until adulthood. He was born full term with a very low birth weight (2400 g=-3.36 standard deviation score, SDS) and length (40.0 cm =-6.53 SDS). At birth he presented with a broad, fleshy nose with anteverted nostrils, thick and patulous lips, a square chin, curvilinear shaped eyebrows without synophrys, short thorax and long slender bones. Then, during childhood tall vertebral bodies, hip dislocation, transverse chest groove, winged scapulae and hyperextensible joints became more evident and the diagnosis of 3-M syndrome was made; this was also confirmed by the finding of a homozygous deletion in exon 18 of the CUL7 gene, which has not been previously described.The patient also exhibited severe GHD (GH <5 ng/ml) and from the age of 18 months was treated with rhGH. Notwithstanding the early start of therapy and good compliance, his growth rate was always very low, except for the first two years of treatment and he achieved a final height of 132 cm (-6.42 SDS).

Figure 1

The patient at one (a), two (b) and three (c) years of age with typical 3-M syndrome facial features including frontal bossing, relatively increased head circumference, triangular face, hypoplastic midface, low nasal bridge, depressed nasal root, fleshy upturned nose, long philtrum, full lips, and pointed, prominent chin.

Figure 2

Patient at 15 (a) and 17.5 (b) years showing facial dismorphism, short stature, broad thorax, sternum carinatum.

Figure 3

Radiographic features of the adult 3-M syndrome patient. On the lateral lumbar spinal radiograph (left panel), vertebral bodies are relatively tall and short. Lumbar hyperlordosis is caused by the short femoral necks. In the central panel, note the short femoral necks with anterior rotation of the pelvis (small foramina obturatoria). The ribs and the visible part of the femoral shafts are slender. The distance between the vertebral pedicles remains constant from L1 to L5. The tibia and fibula (right panel) are relatively inconspicuous. The radiographic features fitting with the diagnosis of 3-M are the tall and narrow vertebral bodies and slender tubular bones; other features of a chondrodysplasia, such as platyspondily or metaphyseal and epiphyseal changes, are typically absent.

Figure 4

Growth chart for height of the patient from birth until adult age. TH=target height.