Goltz syndrome in males: A clinical report of a male patient carrying a novel <i><scp>PORCN</scp></i> variant and a review of the literature

Frisk, Sofia; Grandpeix-Guyodo, Catherine; Silwerfeldt, Karin Popovic; Hjartarson, Helgi Thor; Chatzianastassiou, Dimitris; Magnusson, Irina; Laurell, Tobias; Nordgren, Ann

doi:10.1002/ccr3.1783

Cited by 13 publications

(27 citation statements)

References 25 publications

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“…The majority of them are explained by post-zygotic mutations or chromosomal anomalies (Klinefelter syndrome). Non-mosaic males have also been reported in FDH and IP – respectively about 17% and 45% of the affected males harbour a non-mosaic variant 32 35. In our series, males represented 29% of the patients with a de novo TFE3 variant.…”

Section: Discussionsupporting

confidence: 51%

“…The study of X-inactivation on non-cultured fibroblasts was consistent with functional mosaicism in two affected females with PM who harboured random X-inactivation, whereas a third female without PM had skewed X-inactivation. In IP, FDH and CDPX2, most hemizygous males die in utero; however, there have been reports of surviving males 31–33 with an estimated prevalence around 10% in FDH and IP 32 34. The majority of them are explained by post-zygotic mutations or chromosomal anomalies (Klinefelter syndrome).…”

Section: Discussionmentioning

confidence: 99%

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De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

et al. 2020

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IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

et al. 2020

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“…FDH is an X‐linked dominant disorder caused by loss‐of‐function mutations in the PORCN gene. PORCN is the human homolog of a drosophila polarity gene “porcupine,” located on Xp11.23 . This gene encodes the porcupine protein (46‐aminoacid 52‐kDa endoplasmatic reticulum protein), which is involved in the Wnt signaling and, consequently, with embryonic tissue development .…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, only approximately 35 cases of FDH have been reported in male patients individuals. In addition, variability in the phenotypic severity is observed, which may be determined by mosaicism in female patients or X chromosome inactivation . Usually, there is no family history, since 95% of cases are caused by de novo mutations …”

Section: Discussionmentioning

confidence: 99%

Multiple cutaneous and skeletal abnormalities in an 8‐month‐old boy

Masson

Escobar

Dantas

et al. 2020

Pediatric Dermatology

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An 8-month-old boy presented to the dermatologist for an evaluation of several cutaneous and skeletal abnormalities. Physical examination showed lobster claw deformity (ectrodactyly) of the right hand (Figure 1), hypoplasia of the left leg, and agenesis of the left foot, with areas of skin atrophy and hypopigmentation following Blaschko's lines (Figure 2). On the scalp, areas of patchy alopecia, with sparse hair and cicatricial aplasia cutislike areas could be visualized (Figure 3). In addition, anteroposterior cranial flattening and facial asymmetry were observed. On the left thigh, there were skin-colored exophytic nodules, areas of skin atrophy with hypopigmentation following Blaschko's lines (Figure 4). On the hand, papular exophytic lesions (papillomas) were observed in a linear arrangement, as well as nail deformities, such as longitudinal lines and fissures of the nail blades. On the trunk and extremities, areas of skin atrophy following Blaschko's lines could also be visualized, with punctate erosions within atrophic areas.On general examination, the baby had a normal psychomotor development for his age. Urologic abnormalities were found on imaging, including right renal agenesis, hypospadias, and bilateral cryptorchidism. Furthermore, a cardiologic examination revealed a ventricular septal defect and a patent foramen ovale. Genetic analysis showed a normal male karyotype (46, XY). There was no parental consanguinity, and no other family members were known to have a similar condition.

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“…4,6 Approximately 400 GS cases are reported worldwide; prevalence estimates are unavailable. 7 Ocular manifestations have been reported with varying incidence between 40% and 77% (Table 1), most commonly ocular colobomas, strabismus, and microphthalmia. 1,8,9 The least commonly reported ocular finding in GS is conjunctival and eyelid papillomas (5% in the largest case series).…”

mentioning

confidence: 99%

Papillomas in Goltz syndrome: case report, anaesthetic considerations, and review of the literature

Ruzicki

Nair

Wang

et al. 2019

Canadian Journal of Ophthalmology

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Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

Cited by 13 publications

References 25 publications

De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Multiple cutaneous and skeletal abnormalities in an 8‐month‐old boy

Papillomas in Goltz syndrome: case report, anaesthetic considerations, and review of the literature

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