3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient
© Meazza et al.; licensee BioMed Central Ltd. 2013
Received: 18 January 2013
Accepted: 14 March 2013
Published: 21 March 2013
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).
Keywords3-M syndrome Growth hormone deficiency CUL-7 gene mutation
3-M syndrome (OMIM273750) is a rare autosomal recessive disorder that causes short stature, unusual facial features and skeletal abnormalities . The name of this condition comes from the initials of the three researchers (Miller, McKusik and Malvaux) who first identified it. Individuals affected by 3-M syndrome have intrauterine growth retardation (IUGR) and postnatal growth retardation, worsened also by feeding difficulties during the first years of life. Affected patients usually have a triangle-shaped face with a pointed chin, large ears, full eyebrows, an upturned nose with a fleshy tip, long philtrum, and a prominent mouth with full lips. They may also exhibit prominent shoulder blades and square shoulders, exaggerated curvature of the lower back (hyperlordosis), pectus carinatum or excavatum, prominent heels and other skeletal abnormalities which are apparent in X-ray images .
Mutations in the CUL7 gene cause 3-M syndrome, although genetic heterogeneity has been reported [3, 4] involving two other causative genes, OBSL1 and CCDC8[5–7]. Since CUL7 is involved in chondrocyte growth and proliferation, in 3-M syndrome, reduced cell mitosis during the early gestation period could be the cause of retarded growth. In particular, these mutations disrupt the ability of the protein cullin-7 to bring together the components of the ubiquitine-proteasome system which is involved in the degradation of unwanted proteins. Therefore, impaired ubiquitination may have a role in the pathogenesis of IUGR in humans.
Here, we describe a patient with 3-M syndrome and GH deficiency, who was followed from the age of two years to adulthood. Even though rhGH therapy was started early in infancy (18 months of age) with good compliance, no catch-up growth was observed.
We observed a slight delay in pubertal development; at the age of 13.8 years he showed reduced luteinizing hormone (LH) levels (2.0 IU/L; normal values 6–30 IU/L) and a gonadal volume of about 6 ml. However, at 18 years his gonadal volume was within the normal range (15–20 ml).
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 .
Written informed consent was obtained from patient’s parents for publication of his Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Growth hormone deficiency
Standard deviation score
Intrauterine growth retardation
Insulin-like growth factor-I
The authors are grateful to Ms. Laurene Kelly for English revision of the manuscript.
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