Novel cAMP binding protein-BP (CREBBP) mutation in a girl with Rubinstein-Taybi syndrome, GH deficiency, Arnold Chiari malformation and pituitary hypoplasia

Rubinstein-Taybi syndrome (RTS) is an autosomal dominant disease that occurs in 1 out of 125,000 births. The first description of the syndrome by Rubinstein and Taybi was in 1963 [1].

RTS is characterized by broad and sometimes laterally deviated thumbs and halluces, downslanting palpebral fissures, apparent hypertelorism, long eyelashes, high-arched eyebrows, prominent nose with columella below the alae nasi, malpositioned ears with dysplastic helices, high-arched palate, hypoplastic maxilla. The facial expression is characteristic: showing grimacing or at least unusual smile. The finding of talon cusps at the permanent incisors can be helpful, as these are only rarely found in other entities [2].

Other physical findings may include a variety of congenital heart defects, joint hypermobility and skin anomalies (hirsutism, naevus flammeus on the forehead, and keloid formation) [3]. Mental retardation is usual with an average IQ between 35 and 50, but cognitive functioning outside these limits may occur [4].

Craniospinal and posterior fossa abnormalities have been commonly reported in association with RTS, including large foramen magnum, microcranium, spina bifida occulta, cervical hyperkyphosis, dens hypoplasia, cervical instability of C1-C2, cervical spondylolisthesis and scoliosis [5].

The association between RTS and Arnold-Chiari malformation has been described in four patients, complicated by syrinx in two of them [6‐8].

Affected patients are also characterised by short stature with indirect measures of growth hormone usually found normal. There are no descriptions of growth hormone (GH) deficiency in this syndrome and therefore data on the need, effectiveness, or safety of growth hormone in children with this syndrome are not yet available in literature.

The first descriptions of cytogenetic anomaly in RTS were in 1991 [9‐11]. The syndrome is autosomal dominant but reports of transmission are rare, the overwhelming majority of cases being caused by de novo mutations [12, 13].

The known genetic causes are mutations of the genes CREBBP (OMIM 600140, cAMP-response-element binding protein-BP), located at chromosome 16p13.3 and EP300 (OMIM 602700, E1A-binding protein), a CREBBP homolog, located at chromosome 22q13.2.

CREBBP mutations are found in 50-60% and EP300 mutations in 5% of RTS cases [14, 15]. The CREBBP gene is involved in different signalling pathways and in certain cellular functions, such as DNA repair, cell growth, differentiation, apoptosis and tumor suppression.

The mutational spectrum is represented mainly from frameshift, nonsense, splice site and missense mutations. Less frequently large deletions (of one or more exons) and rarely balanced inversions and translocations have been found. Mutations may remove 5′ or the 3′ end of CREBBP and adjacent genomic segments, which causes the 16p13.3 contiguous gene deletion syndrome [16‐18].

The genetic cause of RTS remains unknown in about 40% of the patients.

RTS is associated with craniocervical and spinal cord complications. In literature patients with RTS affected by os odontoideum, C1-C2 instability, dens hypoplasia, scoliosis, cervical myelopathy, Chiari malformation, tethered spinal cord, large foramen magnum, vertebral fusion, microcranium, craniovertebral junction stenosis have been described [6, 19, 20].

The most serious consequences of Arnold Chiari malformation are attributable to syringomyelia formation with dysesthesias, paresthesias, anesthesias, incontinence, motor weakness, headache, abnormal reflexes as presenting signs [21]. However, our patient did not show any of these symptoms.

Little literature exists linking RTS to the occurrence of Chiari malformation. A case report examined a 2-year-old patient with RTS and a Chiari I malformation without syrinx who presented with a microdelection of 16p13.3 involving the CREBBP gene and additionally ADCY9 and SRL genes. The authors of this article postulated that the Chiari I malformation may be related to a contiguous gene syndrome associating the haploinsufficiency of the neighboring genes to the etiology of Chiari malformation [8]. Another case report involving a 4-year-old Korean-Japanese RTS patient with a genetically confirmed CREBBP gene mutation with a C insertion in exon 31 discovered a Chiari I malformation. No syrinx was described in this patient’s imaging [7].

Finally, a recent case report described 13-year-old identical twin girls with RTS, Chiari malformation and extensive multioculated spinal cord syrinxes. The twins were both confirmed to possess an identical p.Arg2004 gene mutation in the CREBBP gene that is predicted to cause loss of normal protein function through premature protein truncation [6].

Since our patient also had a nonsense mutation in CREBBP leading to a premature stop codon, Chiari malformation and syrinx, this excludes the possibility of a contiguous gene syndrome (RTS + Chiari malformation + syrinx) previously postulated and confirms the single gene effect of CREBBP gene mutation.

This is the first report of GH deficiency in a RTS patient. Indirect measures of growth hormone secretion have usually been reported normal in individuals with RTS in literature [20] but these patients have never been tested for growth hormone deficiency by dynamic testing.

Although the association between growth hormone deficiency and RTS could be coincidental, there are some possible pathogenic links between GH deficiency and RTS. CREBBP mutations could influence growth hormone secretion at multiple levels of the hypothalamic-pituitary-somatomedin axis, including both the hypothalamus and pituitary. A study using conditional cAMP response element binding protein (CREB) mutant mice showed that selective loss of the CREB transcription factor in all the brain except pituitary resulted in reduced postnatal growth consistent with dwarfism caused by GH deficiency and consequent reduction in IGF-1 mRNA expression in the liver. In addition the authors demonstrated that mice with CREB mutation exhibited pituitary hypoplasia. These findings show that CREB is required for the efficient function and development of pituitary probably having an effect at hypothalamic level, as CREB expression in pituitary in this animal model was normal [22, 23]. Since CREBBP is an important CREB co-activator, the possibility exists that also CREBBP mutations at hypothalamic level can play a role in GH deficiency and pituitary hypoplasia. It has been demonstrated that, at pituitary level, CREBBP interacts as cofactor with Pit-1. Pit-1 is an important transcription factor that promotes growth hormone and stimulates somatic growth [24]. Therefore, an impairment of CREBBP/Pit-1 interaction could affect pituitary development and/or GH secrection.