View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Universität München: Elektronischen Publikationen Case Report Cytogenet Genome Res 2015;146:33–38 Accepted: March 26, 2015 DOI: 10.1159/000431389 by M. Schmid Published online: June 19, 2015 2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3 a a a a Yasmin Mehraein Martina Pfob Ortrud Steinlein Eric Aichinger a b b a Marlene Eggert Valerie Bubendorff Adelina Mannhart Stefan Müller a Institute of Human Genetics, University Hospital, Ludwig Maximilian University of Munich, and b kbo – Heckscher-Kinikum gGmbH of Child and Adolescent Psychiatry , Psychosomatics, Psychotherapy, Academic Teaching Hospital of the Ludwig Maximilian University of Munich, Munich , Germany Key Words intellectual deficits and type E brachydactyly typical for clas- 2q37.3 deletion syndrome · Albright hereditary sical AHO syndrome together with distinctive facial dysmor- osteodystrophy · Brachydactyly type E · Schizophrenic phisms not present in the former. Furthermore, one patient psychosis presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an as- sociation between schizophrenia susceptibility and an un- Abstract known gene within the chromosomal region 2q37. 2q37.3 deletion syndrome belongs to the chromosomal © 2015 S. Karger AG, Basel 2q37 deletion spectrum which clinically resembles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachy- Over 115 patients with 2q37 deletion syndrome have dactyly type E, intellectual disability, behavioral problems, been reported, being the result of either isolated deletion/ and variable intellectual deficits. Different from classical microdeletion or monosomy originating from unbal- AHO syndrome, patients with 2q37 deletion syndrome lack anced translocations [Leroy et al., 2013; Ogura et al., renal parathyroid hormone resistance (pseudohypopara- 2014; Jean-Marcais et al., 2015]. The referred symptoms thyroidism) and soft tissue ossification. So far, deletion map- comprise a wide spectrum including intellectual and be- ping or molecular breakpoint analyses of 2q37 have been havioral, skeletal, cardiac, and urogenital anomalies as performed in only few patients. Here, we report on 2 patients well as Wilms tumor, epilepsy, autism, and eczema. Only with 2q37.3 deletion syndrome. In both patients the break- a fraction of these patients manifest typical symptoms point of the 5.5-Mb terminal microdeletion could be nar- of intellectual disability and brachydactyly type E [Al- rowed down to the same ∼ 200-kb interval on 2q37.3 by bright hereditary osteodystrophy (AHO)-like pheno- BAC-FISH and/or array-CGH. Flanking low-copy repeats may type], which is seen in about half of 2q37 monosomic pa- indicate a classical microdeletion syndrome genesis for the tients [Leroy et al., 2013]. Since the monogenic brachy- 2q37.3 microdeletion subgroup. Clinical evaluation revealed dactyly mental retardation syndrome (BDMR) is linked © 2015 S. Karger AG, Basel Yasmin Mehraein 1424–8581/15/1461–0033$39.50/0 Institute of Human Genetics University Hospital, Ludwig Maximilan University of Munich E-Mail [email protected] DE–80336 Munich (Germany) www.karger.com/cgr E-Mail Yasmin.Mehraein @ med.uni-muenchen.de Downloaded by: UB der LMU München 129.187.254.47 - 8/23/2018 2:19:06 PM A B C D Fig. 1. Case 1. A , B Round face, hypoplastic midface with flat nasal short and broad distal phalanges of the thumbs. D Short toes with bridge, broad nasal tip, small, deep set eyes, and mildly dysmor- no obvious type E brachydactyly in the feet. Side findings: slight phic, deep set ears, facial hypertrichosis, and medial flaring of the partial syndactyly of toes II and III and fingers ( C ) and toes ( D ) bushy eyebrows. C Brachydactyly type E in both hands with inho- with very short, everted or ingrown nails. mogeneous shortening of phalanges and metacarpals, especially to dominant mutations in the HDAC4 gene on 2q37, mi- Case Report crodeletion syndrome 2q37 is considered to be a contigu- ous gene syndrome encompassing the HDAC4 gene as Case 1 The 18-year-old woman presented with symptoms of a para- well as possibly several other neighboring genes [Wil- noid schizophrenic psychosis at the psychiatric hospital. Psy- liams et al., 2010]. chotic symptoms had first occurred only few months prior to Although clinical findings are mostly well-document- hospitalization. A mild intellectual impairment with develop- ed, molecular analyses of monosomy 2q37 breakpoints mental delay and learning disability had been observed since ear- with either FISH or microsatellite panels refining the ly childhood. Her intelligence had been measured in the lower normal range of learning disability; however, she earned a sec- monosomic region are only performed in a minority of ondary school degree followed by a 3-year apprenticeship and cases. With respect to the variety of symptoms and pre- finished with a diploma. sumed inter-individual differences in the cytogenetic Facial features were a round face, hypoplastic midface with flat condition, clear phenotype-genotype conclusions are nasal bridge, small, deep set eyes, and mildly dysmorphic, deep set very limited at present. ears. Additionally, facial hypertrichosis and medial flaring of the bushy eyebrows were remarkable ( fig. 1 A, B). Physical examina- Within the 2q37 deletion spectrum, deletion size as tion showed brachydactyly type E in both hands with inhomoge- well as deletion origin of the reported cases vary widely, neous shortening of phalanges and metacarpals and especially including unbalanced translocations, terminal and inter- short and broad distal phalanges of the thumbs ( fig. 1 C). The toes stitial deletions, thus encompassing a rather inhomoge- were short, but there was no obvious type E brachydactyly in the neous molecular cytogenetic group. The 2q37.3 deletion feet ( fig. 1 D). Fingers and toes showed nail anomalies with very short, everted rims or ingrown nails ( fig. 1 C, D). Further physical syndrome presents a subclass of the 2q37 deletion spec- features were myopia, pectus excavates, and uterus bicornis. trum. The family history was unremarkable besides a unilateral Here, we report on 2 further unrelated cases of 2q37.3 broadening and duplication of the terminal phalanx and nail of a deletion with the AHO-like phenotype and intriguing fa- thumb in 1 of 2 otherwise inconspicuous elder brothers. cial dysmorphism. Both patients show true interstitial Case 2 microdeletions assigned to an identical breakpoint in The 32-year-old male patient presented with mild intellectual 2q37.3. We could localize the deletion breakpoints within disability and severe obesity, the latter starting at the age of 12 flanking low-copy repeats, being suggestive for a classical years. Psychomotor and intellectual delay had required ergother- microdeletion syndrome genesis [Stankiewicz and Lup- apy and special schooling. Puberty had been delayed due to hypo- ski, 2010]. Associated clinical features are described and gonadism leading to testosterone substitution from the age of 15 until the age of 20. The patient required special school education. discussed referring to previous reports of 2q37 deletion Neither was he able to graduate with a degree nor to learn a profes- syndrome patients. sion; he was still living at his mother’s home and was unable to take responsibility for his own life. 34 Cytogenet Genome Res 2015;146:33–38 Mehraein/Pfob/Steinlein/Aichinger/ DOI: 10.1159/000431389 Eggert/Bubendorff/Mannhart/Müller Downloaded by: UB der LMU München 129.187.254.47 - 8/23/2018 2:19:06 PM A B C D E Fig. 2. Case 2. A , B Round face, pronounced midface hypoplasia growth. C , D Brachydactyly type E with shortening of metacarpal with flattened nasal bridge, broad nasal tip, deep set eyes with nar- bones III-V as well as various phalanges in both hands. E Feet with- row palpebral fissures, hypertelorism, mildly dysmorphic ears, out brachydactyly but rather small with bilaterally slight shorten- deep frontal hair line, hypertrichosis of the upper facial area, me- ing of the first metatarsal bone pronounced by the relative over- dial flaring of the bushy eyebrows in contrast to the sparse beard length of the second toes. The patient showed striking facial dysmorphism exhibiting a Results round face, pronounced midface hypoplasia with flattened nasal bridge, deep set small eyes, which appeared almost squinted, hy- Conventional chromosome analysis on a 550 band pertelorism, and mildly dysmorphic ears. A deep frontal hair line and general hypertrichosis of the upper facial area were observed; level showed a normal 46,XX and 46,XY karyotype in the eyebrows showed medial flaring and appeared rather bushy case 1 and 2, respectively. In patient 2, a microdeletion being in contrast to the sparse beard growth (fig. 2 A, B). 22q11.2 was excluded by FISH analysis, but FISH using Physical examination revealed brachydactyly type E with short- 2q subtelomeric probes (2q TelVysion; Abott Molecu- ening of metacarpal bones III–V as well as various phalanges in lar) detected a heterozygous terminal microdeletion both hands ( fig. 2 C, D). The feet did not show apparent brachy- dactyly but were rather small (5–10th percentile) in comparison to 2q37 in both cases. Further iterative BAC-FISH analyses the body length