Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly/intellectual disability characterized by growth and psychomotor development delays, hallux thumbs, characteristic facial dysmorphisms with down slanting palpebral fissures, thin upper lip, high nasal bridge, arched eyebrows, micrognathia and a higher risk of tumour formation. RSTS type 1 (RSTS-1) is caused by variants of CREBBP encoding CREB-binding protein which act as transcriptional co-activators and variants of its paralog EP300 that code for E1A associated protein p300 results in RSTS type 2 (RSTS-2). CREBBP and EP300 mutations have been identified in majority (50-60 %) and minority (3-5 %) of RSTS affected individuals. It is a rare autosomal dominant disorder that affects 1 in 300,000 births. Rare diseases (RDs) are progressive, chronically debilitating and/or life-threatening heterogeneous clinical conditions that affect a limited fraction. In this article, we report a case of Rubinstein-Taybi syndrome type 1, a six-year-old boy (proband) belonging to Srinagar district of the Union Territory of Jammu and Kashmir (J&K), India established on the basis of phenotypic symptoms and radiological findings. Whole Exome Sequencing and further Array Comparative Genome Hybridization confirmed the presence of a de novo copy number variation with a 261 kb heterozygous microdeletion present on 16p13.3 cytoband (Chr16:3,694,760-3,955,374) (GRCh37/hg19) spanning three genes DNASE1 (OMIM #125505), TRAP1 (OMIM# 606219) and CREBBP (OMIM# 600140) in the proband only and missing in parents. This is a novel de novo microdeletion being reported for the first time. Haploinsufficiency resulting from copy number loss, indicated by 0.78-fold decreased expression of the CREBBP gene in patient compared to parents is resulting in the development of the disease.

Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB-binding protein (CREBBP) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2-related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Clinicians need more clinical and genetic evidence to detect and comprehend the phenotypic spectrum of this disorder. Exome sequencing was used to identify the disease-causing variants in two affected families A and B from District Kohat and District Karak, Khyber Pakhtunkhwa. Affected individuals from both families presented symptoms of ID, developmental delay and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A>G; NP_004371.2: p.Lys1524Arg) in the CREBBP gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605 + 1G>A) in the TANGO2 gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild-type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function. RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype-phenotype associations.

Rubinstein-Taybi syndrome (RSTS) is a chromosomal segment 16p13.3 microdeletion syndrome and is characterized by CREBBP gene mutations, delay in the development of height and weight, distinctive facial features, broad and sometimes angulated thumbs and halluces, short stature, and intellectual impairment that is mild to extreme. Current literature emphasizes mainly medical, dental, and psychiatric issues in RSTS and there is no retrievable literature on physiotherapy and its role in improving motor function in RSTS. The present case report is of a baby girl of 17 months suspected case of RSTS, presented with all the features of RSTS. Delay in the acquisition of skills and development were the chief complaints. We designed a 12-week treatment regimen that concentrated mainly on transitions using principles of neurodevelopmental therapy. Gross motor function measure (GMFM 88) was taken pre- and post-treatment which showed tremendous improvement. This is the first study on the role of physiotherapy in RSTS.

A complete ophthalmic examination is not routinely performed on infants with Miller-Dieker syndrome (MDS, chromosome 17p13.3 microdeletion). The authors present the cases of four cousins with MDS who also carried a 16p13.3 microduplication (not associated with Rubinstein-Taybi syndrome). Retinopathy of prematurity-like proliferative peripheral retinopathy (PPR) was detected in two male first cousins, but was not detected in the female half-cousins. PPR in the first infant resolved by 4 months, but the second infant's PPR progressed, requiring photocoagulation followed by lens-sparing vitrectomy. While ocular abnormalities are more prevalent and severe in other lissencephalopathies, the PPR in these MDS infants underscores the sight-saving potential of performing an ophthalmologic exam with early molecular testing for all lissencephaly infants.