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Advances in dermatology and venereology Acta Dermato-Venereologica
A Postzygotic SMO Mutation Caused the Original Case of Happle-Tinschert Syndrome
Martin ZENKER 1 , Sigrid TINSCHERT 2 , 3 , Ilse WIELAND 1 , Denny SCHANZE 1 and Rudolf HAPPLE 4
1
Institute of Human Genetics , University Hospital Magdeburg , Otto-von-Guericke University , Leipziger Str . 44 , DE-39120 Magdeburg , 2 Medical Faculty Carl Gustav Carus , Technical University , Dresden , Germany , 3 Division of Human Genetics , Medical University of Innsbruck , Austria , and 4 Deparment of Dermatology , Medical Center – University of Freiburg , Germany . E-mail : martin . zenker @ med . ovgu . de Accepted Jan 15 , 2018 ; Epub ahead of print Jan 16 , 2018
In 2008 , we delineated a distinct sporadically occurring syndrome in the form of segmentally arranged basaloid follicular hamartomas with osseous , dental and cerebral anomalies ( 1 ). The reported patient was a 39-year-old man with multiple skin tumours that showed , in part , comedo-like plugging and were arranged in a unilateral , systematized pattern following Blaschko ’ s lines ( Fig . 1a ). The patient ’ s ipsilateral ( right ) leg was 22.5 cm shorter than the left leg . Rudimentary preaxial polydactyly was noted on the left hand and right foot . The right maxillary teeth were hypoplastic . Moreover , the right side of his chest was rather hairless , and linear areas of atrophoderma and hyperpigmentation involved the right arm and lower leg . Eight similar cases were found in the literature , and we argued that this disorder should not be conflated with mosaic forms of Gorlin syndrome ( 1 ). Subsequently , several similar cases were reported ( 2 – 6 ), and the name “ Happle-Tinschert syndrome ” ( HTS ) was proposed ( 2 ).
In 2016 , Khamaysi et al . ( 7 ) reported an activating SMO mutation in what they believed to represent a mosaic form of Gorlin syndrome . In a Letter to the Editor ( 8 ), we argued that their patient did not have “ segmental basal cell naevus syndrome ”, but HTS . Moreover , we suggested that HTS may turn out to be a clinical variant of Curry-Jones syndrome ( CJS ) that is likewise caused by postzygotic SMO mutations ( 9 ). In their reply , however , Khamaysi et al . ( 10 ) upheld their opinion that the presented case belonged to the spectrum of Gorlin syndrome because the patient “ displayed diagnostic criteria for Gorlin syndrome but not for HTS or CJS ”.
Meanwhile , we had the opportunity to analyse the SMO gene in DNA from a native cryoconservated tissue sample obtained from a skin area with basaloid follicular hamartomas of the original HTS patient reported in 2008 ( 1 ). Genotyping was performed by standard Sanger sequencing . As demonstrated in Fig . 1b , we could identify the sequence change c . 1234C > T in the DNA sample . The fraction of mutated DNA was calculated to be 20 – 30 %, thus suggesting a mosaic status . The observed mutation predicts the missense change p . Leu412Phe in the SMO protein and is the known recurrent SMO mutation that had been found in CJS ( 9 ) and in the patient reported by Khamaysi et al . ( 7 ). These findings corroborate our previous hypothesis that HTS is indeed caused by mosaic SMO mutations and represents a variant of CJS . We therefore postulate that the phenotype reported by Khamaysi et al . ( 7 ) belongs to this spectrum of sporadically occurring mosaic SMO disorders .
Fig . 1 . Happle-Tinschert syndrome . ( a ) Unpublished photograph of multiple basaloid follicular hamartomas in the original case from 2008 ( 1 ). ( b ) Demonstration of the mosaic SMO mutation c . 1234C > T ( p . Leu412Phe ) in lesional tissue from the patient .
The authors have no conflicts of interest to declare .
REFERENCES
1 . Happle R , Tinschert S . Segmentally arranged basaloid follicular hamartomas with osseous , dental and cerebral anomalies : a distinct syndrome . Acta Derm Venereol 2008 ; doi : 10.2340 / 00015555-2883 Acta Derm Venereol 2018 ; 98 : 534 – 535
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica .