Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome due to disruption of BPTF in a 35‐year‐old man initially diagnosed with Silver‐Russell syndrome

Abstract

To the Editor: We present a 35-year-old male with a de novo reciprocal chromosomal translocation (RCT) t(1;17)(q24.3;q24.2) reported in 1993 as the second observation of Silver-Russell syndrome (SRS) (MIM#180860) following the report by Ramírez-Dueñas et al. Subsequent FISH and molecular studies, performed before the release of the human reference genome in 2001, indicated a disruption of KPNA2 (MIM*600685) at 17q24.2. However, no mutation in the group of 31 SRS patients was found. Using fluorescence in situ hybridization (FISH), wholegenome and Sanger sequencing we found that the 17q24.2 breakpoint maps at chr17:65,947,981-65,952,868 (hg19) (deletion of 4.9 kb) in intron. 25 of the dosage sensitive Bromodomain PHD finger transcription factor (BPTF) gene (NM_004459.6) (pLI = 1.00) (Figure 1J,K), recently described as responsible for Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) (MIM#617755). The 1q24.3 breakpoint maps to chr1:172,228,493-172,234,072 (deletion of 5.5 kb) within the loss-of-function tolerant (pLI = 0.03) brain specific DNM3.No non-polymorphic copy number variants (CNVs) were identified by chromosomal microarray analysis (CMA). We found that following morphological features have not changed with age: short asthenic stature, hemihypotrophy, poorly developed muscles, microcephaly, asymmetric triangular face, hypertelorism, broad, lateral flaring of the eyebrows, protruding eyeballs, broad palpebral fissures, long eyelashes, long nasal bridge, prominent nose, asymmetric zygomatic region, micrognathia, thin upper lip, mandibular retrognathia, microglossia, high palate and protruding ears of different size and asymmetric location. The facial asymmetry is now more pronounced with more cis-frontal profile, more protruded nose, maxilla and mandible distorted into right side, narrowing maxillary and mandible arcus and anodontia (Figure 1A-D). Skeletal deformities include advanced cervical and thoracic scoliosis in the convex right direction, narrowed intervertebral foramens and canal of lumbosacral spine L4-L5-S1 (Figure 1G), the facet joints arthrosis, hypoplastic styloid process of ulnar bone, hallux valgus, pes planus and clinodactyly of 5th finger with shorter distal and medium phalanges (Figure 1E,H). In addition, broad big toes with shortening of proximal phalanges, partial skin syndactyly of the 2nd and 3rd toes, and sandal gap bilaterally were observed (Figure 1F,I). Quantitative bone and body composition analysis performed using dual-energy X-ray absorptiometry equipment showed excess in total body fat mass (Fat Percentage 26.3%) corresponding to 92nd centile with reference to the healthy male population. The android/gynoid ratio in fat distribution was 0.71, indicative of a deteriorated pattern of adiposity and a relative predominance of gynoid fat tissue. The perceptual and acoustic assessment of the voice showed the disorders of voice quality (dysphonia), including hoarseness, roughness, and fatigue were likely caused by the disturbance of vocal folds vibrations and insufficiency of glottal closure. Logopedic assessment showed the defect of phonemic audition with dyslexia, but not dysgraphy or acalculia observed previously. Finally, myopia with concomitant divergent strabismus were found. The boy was small for gestational age presenting with postnatal growth failure, body asymmetry and feeding difficulties, although further two signs of SRS according to the Netchine-Harbison score were not present (Tables S1,S2). Psychomotor and speech delay, dysmorphism, and limbs anomalies are similar to the features reported in the NEDDFL subjects. 5 We propose that BPTF testing should be considered in the diagnostic workup of SRS. This is the first description of NEDDFL phenotype in the adult person.