3-M dwarfism is a clinical entity which is not often recognized in childhood. Here, we describe a patient with 3-M syndrome associated with GHD. The child was very small at birth and severe growth restriction continued in the post-natal period and throughout childhood. In fact, his final stature is −6.42 SDS. In our patient, skeletal changes typical of 3-M syndrome, such as long slender bones, tall vertebral bodies, triangular-shaped face with square chin, short thorax, transverse chest groove and winged scapulae were not present at birth, but manifested in the course of childhood. Therefore, the diagnosis of 3-M syndrome was made only when the patient was 17 year-old, after having investigated other potential syndromes such as hypocondroplasia. However, an early diagnosis is important for familial genetic familiar counselling since 3-M syndrome has an autosomal recessive mode of inheritance. It is important to closely follow patients with syndromic features and perform genetic analyses as the dismorphic features become apparent.
3-M dwarfism belongs to a group of intrauterine growth retardation-malformation syndromes. Therefore, differentiation from Russell-Silver syndrome is difficult because of the phenotypic variability of the latter. Body asymmetry is not present in 3-M syndrome, while short stature with prenatal onset and a small triangular face are found in both syndromes. However, 3-M subjects are shorter than those with Russell-Silver syndrome [8, 9].
The most striking feature of 3-M syndrome is severe growth retardation. According to other cases reported in the literature, the present patient achieved a height between 4 and 6 SD below the mean . Since our patient also exhibited severe GHD, rhGH therapy was started. To the best of our knowledge only one other case of partial GH deficiency in a 3-M syndrome patient has been described . However, in the six cases described by van der Wal et al. , five patients were treated with rhGH independently from normal GH secretion, but only the two patients who started GH treatment at a prepubertal stage showed a good response and their adult height was well above the final height of the other three cases. On the other hand, Russell-Silver syndrome patients benefit from GH supplementation even in the absence of GHD  and show significant growth acceleration and improved final height, even when GH therapy is initiated later in life . In our patient, even though rhGH therapy was started early in infancy (18 months of age) with good compliance, no catch-up growth was observed. His slow growth continued throughout childhood and adolescence leading to a final height of 132 cm, well below his target height. Our patient’s blunted response to rhGH therapy may be due to the presence of the mutation in the CUL7 gene which may strongly affect GH effects on longitudinal growth. In fact, it has been reported that subjects with CUL7 mutations are significantly shorter than those with OBSL1 or CCDC8 mutations .
Finally, we observed a rather normal sexual development confirming that male gonadal dysfunction is not a concomitant feature of 3-M syndrome, as also reported in previous studies .
In conclusion, there are many typical features of 3-M syndrome, but, apart from a very severe growth retardation, patients may not exhibit these from birth. Many other syndromes with short stature should be considered when making a differential diagnosis of 3-M syndrome, i.e. Silver-Russel syndrome, Bloom syndrome, Dubowitz syndrome, Rubistein-Taybi syndrome, Floating-Harbor syndrome, Mulibrey nanism and fetal alcohol syndrome, but the most difficult to differentiate is Silver-Russel syndrome. However, during childhood, subjects with 3-M syndrome develop striking radiological abnormalities, making the diagnosis possible. Finally, the diagnosis should be confirmed by the presence of mutations in the CUL7 gene, which account for about 80% of 3-M syndrome patients .