Authors: Franziska Hopfner MD, Almuth Caliebe MD, Günther Deuschl MD and Susanne A. Schneider MD, PhD
Article first published online: 24 SEP 2014 | DOI: 10.1002/mdc3.12085
Tricho-rhino-phalangeal syndrome (TRPS type 1; MIM 190350) is a rare autosomal dominant disorder clinically characterized by craniofacial and skeletal malformation. Typical features include a short stature, sparse, slowly growing scalp hair and sparse eyebrows, a bulbous tip of the nose, and protruding ears. A long, flat philtrum and a thin upper vermillion border are highly characteristic. The most typical radiographic findings in TRPS are cone-shaped epiphyses, predominantly at the middle phalanges. Genetic testing typically identifies rare variants in TPRS1, located on 8q24.12, but occasional complete or partial loss of a gene copy or a chromosome abnormality, such as translocation or inversion disrupting the gene, have been described.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by tremor, muscle rigidity and bradykinesia with a lifetime risk of 1% to 2%. Onset is typically late in life, but onset before age 50 occurs in approximately 4% of cases. Young-onset parkinsonism has a strong genetic basis of which approximately two thirds can be genetically clarified. However, there remain a proportion of unsolved cases with yet rarer genetic cause.
We report on a case with both TRPS and a young-onset levodopa-sensitive parkinsonian syndrome. We propose that this co-occurrence is unlikely to be coincidental and that levodopa-sensitive parkinsonism may represent another feature of TRPS.
This 42-year-old male Caucasian had a normal birth; however, early milestones were delayed with walking difficulties, numerous bone fractures, deformed fingers, necrosis of the femoral head, and a heart valve defect. In puberty, he developed alopecia. A short stature was noted. At age 35, he developed an levodopa-sensitive left hand resting tremor, rigidity, and bradykinesia and was diagnosed with a parkinsonian syndrome. Within a few years, he developed severe levodopa-induced dyskinesias with fluctuations and end-of-dose akinesia. Therefore, at age 40, he underwent DBS surgery with excellent response.
His family history was negative for parkinsonism; there was no consanguinity. His sister, mother, and maternal grandmother, however, shared the features of craniofacial and skeletal malformation (see Figs. 1 and 2 for pedigree and facial features), suggesting an autosomal-dominant mode of inheritance. Genetic testing was negative for alterations in Parkin (PARK2), PINK1 (PARK5), and DJ1 (PARK7). However, Sanger sequencing of TPRS1 (GenBank NM_014112.2, NC_000008.10) revealed a truncating mutation c.2602_2605dupGGGG p.A869GfsX27 in the heterozygous state. TPRS1 codes for a zinc finger transcription factor that represses GATA-regulated genes and binds to a dynein light-chain protein. Binding of the encoded protein to the dynein light-chain protein affects binding to GATA consensus sequences and suppresses its transcriptional activity. TRPS1 expression is found in cartilage condensations, hair follicles, and other tissues. In mice, a complex pattern of expression is also found in the developing brain.
Figure 1. The index case was genetically tested (marked by the asteriks) as mutation carrier of TRPS. YOPD = young-onset PD.
Figure 2. Pathognomonic facial features of TRPS: The index patient (left) demonstrates a prominent nose, a thin upper lip, a long flat philtrum, and prominent ears. He has alopecia and thin lateral eyebrows. Typical bone deformities include short, deformed fingers (right, here shown in the mother).
Neurological symptoms associated with TRPS include epilepsy. However, this is mostly observed in patients with deletions. To our knowledge, this is the first report of early-onset levodopa-sensitive parkinsonism in a patient with TRPS. Co-occurrence of these two relatively uncommon conditions in the same patient is unexpected. The prevalence of clinically recognized TRPS is very low, supposing that less than 7.5 per 10,000 people are affected. Young-onset levodopa-sensitive parkinsonian syndromes occur in approximately 32 per 10,000. Assuming that both samples are independent, the likelihood of a co-ocurrence of both is 240 per billion. This suggests a possible etiological association. Mutations in Parkin, PINK1, and DJ1 known to cause early-onset PD were excluded, and we propose that this levodopa sensitive parkinsonian syndrome may be a possible feature of TRPS. Identification of further cases with parkinsonian features in patients with TRPS will help to confirm an association between this genetic syndrome and parkinsonism.