Severe growth hormone deficiency and pituitary malformation in a patient with chromosome 2p25 duplication and 2q37 deletion
- Annalisa Vetro†1,
- Sara Pagani†2,
- Margherita Silengo3,
- Mariasavina Severino4,
- Elena Bozzola5,
- Cristina Meazza2,
- Orsetta Zuffardi6 and
- Mauro Bozzola2, 7Email author
© Vetro et al.; licensee BioMed Central Ltd. 2014
Received: 18 February 2014
Accepted: 27 May 2014
Published: 19 June 2014
We report on a male child ascertained at 4.8 years of age with severe growth failure, growth hormone (GH) deficiency, psychomotor delay with prevalent speech impairment, and a distinct phenotype. An evaluation of his hypothalamic-pituitary region by Magnetic Resonance Imaging (MRI) revealed pituitary hypoplasia with pituitary stalk interruption and ectopic posterior pituitary lobe, which are considered prognostic markers of permanent GH deficiency. Prenatal chromosome analysis because of increased nuchal translucency revealed a normal male karyotype, whereas postnatal high resolution banding raised the suspicion of a 2q abnormality. Subsequently, array Comparative Genomic Hybridization (array-CGH) revealed a de novo complex genomic rearrangement consisting of a 2p25 duplication and a 2q37 deletion: arr[hg19] 2p25.3p25.1(30,341-9,588,369)x3,2q37.2q37.3(235,744,424-243,041,305)x1. FISH analysis showed that the abnormal chromosome 2 mimicked the derivative of an inversion with the duplicated 2p region located distally at 2q. This is, to the best of our knowledge, the first case with distal 2p25 duplication and 2q37 deletion and pituitary malformation leading to GH deficiency.
Keywords2p duplication 2q deletion Growth hormone deficiency Pituitary hypoplasia
The overall frequency of sub-microscopic causative deletions and duplications detected by chromosomal microarrays (CMA) in patients with intellectual disability/multiple congenital malformations, is around 15-20%, significantly higher in respect to that provided by conventional karyotyping.
Chromosome 2q37 deletion has been reported in more than 100 patients most of whom display short stature, obesity, brachydactily and intellectual deficiency, which are also observed in Albright syndrome. The HDAC4 gene has notably been established as responsible for brachymetaphalangy and intellectual deficit observed in these individuals[2, 3]. Distal 2p duplication has also been reported although much more rarely and mostly in the context of inv dup 2p syndrome[4, 5]. The clinical phenotype includes pre- and post-natal growth retardation, psychomotor delay, facial dysmorphism and, less frequently congenital heart malformations. To our knowledge only three subjects have been reported to have both the 2q deletion and 2p duplication two resulting de novo and one being the derivative of a maternal pericentric inversion[6, 7]. Due to the complexity of the chromosomal rearrangement and its rarity, a clinical diagnosis of this condition is almost impossible. Here, we report on a four year-old child harboring a de novo 2p25 duplication and 2q37.1-qter deletion presenting with severe psychomotor delay and complete GH deficiency due to pituitary hypoplasia. The molecular diagnosis had been significantly delayed since prenatal cytogenetics analysis, performed to investigate increased fetal nuchal translucency, resulted in a normal male karyotype. As a consequence, the patient’s condition in his early infancy was attributed to a Mendelian syndrome.
The propositus was the second child of healthy non-consanguineous Italian parents. His father and mother were 40 and 37 years old, respectively. Ultrasound scan at the 22nd week of gestation revealed an increased fetal nuchal translucency, while the amniocentesis showed a normal 46,XY fetal karyotype. The patient was born at term (40 weeks) by spontaneous vaginal delivery. The birth weight was 3340 g (0.51 SD), birth length 50 cm (0.53 SD), and OFC 36 cm (0.50 SD). Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. Family history was unremarkable. The father’s height was 165.8 cm and the mother’s height was 148.5 cm with a mid-parental height of 163.5 cm. His eight year-old sister was healthy.
Both 2p duplications and 2q deletions are usually observed as part of more complex duplication/deletion syndromes, being distal imbalances frequently associated with the unbalanced segregation of a reciprocal translocation present in one parent or, more rarely, arisen de novo in the early embryo. Obviously, the presence of two different imbalances, involving several genes at once, makes clear genotype-phenotype correlations more difficult and renders the recognition of the syndrome on clinical grounds almost impossible. Complex rearrangements involving a terminal short arm duplication and a terminal long arm deletion of the same chromosome may result from meiotic recombination of a parental pericentric inversion as in one patient reported by Armstrong et al., 2005. However many of these cases are the result of a de novo event, suggesting that the rearrangement may occur in two steps, the first resulting in a terminal deletion lately repaired by the capture of the telomere of the opposite arm, thus resulting in its duplication[9, 11]. In our case both parents had a normal karyotype, suggesting that the rearrangement most likely occurred through this mechanism.
In the literature only three viable patients with both a short arm duplication and long arm deletion of chromosome 2 have been reported[6, 7], two of them sharing with our patient short stature, mild trigonocephaly, ptosis, low set ears, micrognathia, fleshy fingertips, scoliosis and abnormal hearing. In the third case, in which the extent of 2p duplication was not assessed, developmental delay, short stature and dolichocephaly were reported. Phenotypic findings in patients with chromosome 2q terminal deletions correlate in some cases with breakpoints positions[2, 12], although in many cases genotype–phenotype correlations have been impaired by the lack of molecular analysis or by the presence of a translocation derivative. However, almost all patients have moderate to severe developmental delay, short stature, obesity and brachymetaphalangy[2, 12, 13]. The latter, together with short stature, is characteristic of the Albright’s hereditary osteodystrophy-like (AHO-like) syndrome in patients with 2q37 deletions. Haploinsufficiency for the HDAC4 (Histone deacetylase 4) gene has been proposed as responsible for the observed brachymetaphalangy and intellectual disability, with both deletions and truncating mutations reported in association to this phenotype. Although short stature seems to be a common trait for both 2q terminal deletions or 2p distal duplications, the presence of associated endocrinological defects has been rarely reported, and we are aware of only two reports of GH-deficiency in patients with a 2q37 deletion[13, 14]. We were not able to find any cases of pituitary stalk interruption in patients with similar rearrangements, either searching the literature or in public databases such as DECIPHER. In our patient 26 and 61 protein coding genes are respectively duplicated or deleted. Even using prioritization tools (Endeavour, ToppGene), we were not able to find a convincing candidate for his pituitary defect. Moreover, no pituitary-specific expression is reported for any of the candidates. We can speculate that in the non-deleted chromosome, a gene necessary for the proper pituitary development is mutated, possibly unmasking a recessive condition.
In conclusion, this is the first case of distal 2p duplication and 2q deletion with severe short stature and pituitary hypoplasia, interrupted pituitary stalk and an ectopic posterior pituitary lobe. These findings are considered prognostic markers of permanent GH deficiency as detected in our patient and may be associated with other hormonal defects causing variably severe panhypopituitarism not present in our case. The diagnosis of GH deficiency was confirmed by the significant increase in growth rate after substitutive GH therapy.
Written informed consent was obtained from the patient’s parents for the publication of this report and any accompanying images.
Magnetic Resonance Imaging
Comparative Genomic Hybridization
Fluorescent In Situ Hybridization
Insulin-like Growth factor I
Standard deviation score.
The authors are grateful to Laurene Kelly for English revision of the paper.
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