Decoding Mosaicism: Unraveling the Mystery of PTCH1 Variants in a Novel Neurocutaneous Syndrome
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
This case highlights a patient with an unexplained constellation of neurocutaneous findings, who has undergone extensive germline and somatic genetic testing with no definitive diagnosis.
Case Presentation
Our patient is a now 23 m.o. male with a history of congenital hemihypertrophy, torticollis, asymmetric brainstem malformation, cryptorchidism, nevus psiloliparus of the right cheek and scalp, facial skin tags, subcutaneous calcified nodules of the left back with overlying hypopigmented atrophic lesions, multiple medium-sized blue/grey nevi (versus dermal melanocytosis) extending linearly down the right back with central areas of atrophy and calcified nodules, right hearing loss secondary to a cholesteatoma versus lipoma, and global developmental delays. The differential diagnosis for this patient includes encephalocraniocutaneous lipomatosis, SCALP (Sebaceous nevus-CNS malformations-aplasia cutis congenita-limbal dermoid-pigmented nevus) syndrome, or a novel mosaic neurocutaneous syndrome.
Diagnostic Workup
Biopsies were obtained from a right back lesion, right eye lesion, and right lower lip lesion which were notable for dermal melanocytosis, epidermal acanthosis with parakeratosis, and mild epidermal acanthosis, respectively. Karyotype and whole exome sequencing analysis were performed, both of which were normal. Tissue remaining from biopsy of the right eye lesion was sent to a lab capable of detecting variants with a variant allele frequency as low as 1%. Results from the custom gene panel (46 genes including FGFR1 and KRAS) identified two pathogenic variants in PTCH1: c.1728+1G>T (15.6% allele frequency) and c.2511_2512delinsTT (p.Lys838*) (18.6% allele frequency). Targeted mosaic variant testing on blood was sent for both variants, with the p.Lys838* variant being possibly present at 1% allele frequency; however, the possibility of a sequencing artifact cannot be ruled out. At this time, it remains unknown if these variants are in cis, trans, or in the same cell line. New biopsies are to be collected from the patient’s back lesions in November, on which we plan to repeat the custom somatic gene panel to further clarify the genetic complexities of this case.
Treatment and Management
Germline pathogenic variants are associated with Gorlin syndrome, also known as Basal Cell Nevus Syndrome (BCNS). The patient does not meet clinical criteria for BCNS at this time; however, majority of the major features of this condition are not congenital. Precautionarily, we have considered following screening guidelines for BCNS until additional testing is completed or new clarifying information arises. The left back lesions are bothersome and will be surgically excised in November.
Outcome and Follow-Up
Follow-up and additional recommendation will be dependent on the results of the pending additional genetic testing.
Discussion
To our knowledge, germline and somatic PTCH1 loss-of-function variants have never been reported with a phenotype other than BCNS. Many of the clinical findings of BCNS such as basal cell carcinomas, keratocystic odontogenic tumors, and medulloblastoma are consequences of a somatic “second-hit;” however, they occur postnatally. It is possible that the patient’s variants both arose during embryogenesis and follow a variation of type 2 segmental mosaicism. Type 2 segmental mosaicism has been reported in other neurocutaneous disorders such as neurofibromatosis type 1 and tuberous sclerosis. A single care report (PMID: 23746055) of type 2 segmental mosaicism in Gorlin syndrome has been reported. However, without evidence of our patient’s PTCH1 variants being present in more than one lesion, we cannot confidently come to this conclusion.
Conclusion
As technological advancements have only recently been capable of detecting mosaic variants at such low variant allele frequencies on a clinical basis, it is not uncommon for individuals with mosaic disorders to remain undiagnosed. This case underscores the complexities involved in diagnosing rare mosaic syndromes. A more detailed exploration of the relationship between somatic PTCH1 variants and alternate phenotypes is warranted if the additional genetic studies yield similar results.
This case highlights a patient with an unexplained constellation of neurocutaneous findings, who has undergone extensive germline and somatic genetic testing with no definitive diagnosis.
Case Presentation
Our patient is a now 23 m.o. male with a history of congenital hemihypertrophy, torticollis, asymmetric brainstem malformation, cryptorchidism, nevus psiloliparus of the right cheek and scalp, facial skin tags, subcutaneous calcified nodules of the left back with overlying hypopigmented atrophic lesions, multiple medium-sized blue/grey nevi (versus dermal melanocytosis) extending linearly down the right back with central areas of atrophy and calcified nodules, right hearing loss secondary to a cholesteatoma versus lipoma, and global developmental delays. The differential diagnosis for this patient includes encephalocraniocutaneous lipomatosis, SCALP (Sebaceous nevus-CNS malformations-aplasia cutis congenita-limbal dermoid-pigmented nevus) syndrome, or a novel mosaic neurocutaneous syndrome.
Diagnostic Workup
Biopsies were obtained from a right back lesion, right eye lesion, and right lower lip lesion which were notable for dermal melanocytosis, epidermal acanthosis with parakeratosis, and mild epidermal acanthosis, respectively. Karyotype and whole exome sequencing analysis were performed, both of which were normal. Tissue remaining from biopsy of the right eye lesion was sent to a lab capable of detecting variants with a variant allele frequency as low as 1%. Results from the custom gene panel (46 genes including FGFR1 and KRAS) identified two pathogenic variants in PTCH1: c.1728+1G>T (15.6% allele frequency) and c.2511_2512delinsTT (p.Lys838*) (18.6% allele frequency). Targeted mosaic variant testing on blood was sent for both variants, with the p.Lys838* variant being possibly present at 1% allele frequency; however, the possibility of a sequencing artifact cannot be ruled out. At this time, it remains unknown if these variants are in cis, trans, or in the same cell line. New biopsies are to be collected from the patient’s back lesions in November, on which we plan to repeat the custom somatic gene panel to further clarify the genetic complexities of this case.
Treatment and Management
Germline pathogenic variants are associated with Gorlin syndrome, also known as Basal Cell Nevus Syndrome (BCNS). The patient does not meet clinical criteria for BCNS at this time; however, majority of the major features of this condition are not congenital. Precautionarily, we have considered following screening guidelines for BCNS until additional testing is completed or new clarifying information arises. The left back lesions are bothersome and will be surgically excised in November.
Outcome and Follow-Up
Follow-up and additional recommendation will be dependent on the results of the pending additional genetic testing.
Discussion
To our knowledge, germline and somatic PTCH1 loss-of-function variants have never been reported with a phenotype other than BCNS. Many of the clinical findings of BCNS such as basal cell carcinomas, keratocystic odontogenic tumors, and medulloblastoma are consequences of a somatic “second-hit;” however, they occur postnatally. It is possible that the patient’s variants both arose during embryogenesis and follow a variation of type 2 segmental mosaicism. Type 2 segmental mosaicism has been reported in other neurocutaneous disorders such as neurofibromatosis type 1 and tuberous sclerosis. A single care report (PMID: 23746055) of type 2 segmental mosaicism in Gorlin syndrome has been reported. However, without evidence of our patient’s PTCH1 variants being present in more than one lesion, we cannot confidently come to this conclusion.
Conclusion
As technological advancements have only recently been capable of detecting mosaic variants at such low variant allele frequencies on a clinical basis, it is not uncommon for individuals with mosaic disorders to remain undiagnosed. This case underscores the complexities involved in diagnosing rare mosaic syndromes. A more detailed exploration of the relationship between somatic PTCH1 variants and alternate phenotypes is warranted if the additional genetic studies yield similar results.
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