Phacomatosis pigmentokeratotica and precocious puberty associated with
            <i>
              <scp>HRAS</scp>
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            mutation

Martin, R. J.; Arefi, M.; Splitt, Miranda; Redford, Lisa; Moss, Celia; Rajan, Neil

doi:10.1111/bjd.15643

Cited by 13 publications

(13 citation statements)

References 7 publications

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“…is mutation leads to a constitutive activation of MAPK and PI3K-Akt cell signaling pathways, which translates into a higher rate of cell proliferation favoring the development of complex hamartomas in the skin and other organs [9,11,13].…”

Section: Discussionmentioning

confidence: 99%

Association of Central Precocious Puberty with a Rare Presentation of Schimmelpenning–Feuerstein–Mims Syndrome in a Peruvian Girl

Torre

Villar

Lama

et al. 2020

Case Reports in Endocrinology

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Schimmelpenning–Feuerstein–Mims syndrome (SFM), an epidermal nevus syndrome characterized by skin lesions, has an estimated incidence of 1 per 10 000 live births. Nevus sebaceous, the most common cutaneous lesion, and verrucous nevus, the less frequent lesion, are coupled with a wide range of extracutaneous manifestations. As part of these manifestations, rarely, central precocious puberty can arise. We report the case of a 1-year-5-month-old girl who presented to the Endocrinology and Metabolism Department with breast enlargement that began at one year of age, growth of pubic and axillary hair three months later, and vaginal bleeding that occurred five months later. During clinical examination, melanocytic nevi, with a diameter ranging from 3 to 5 mm, were noted on the face. Verrucous nevi of variable size with a tendency for coalescence following the lines of Blaschko and melanocytic nevi with a diameter ranging from 3 to 6 mm were observed on the right hemibody and on the left hemibody, respectively. Right asymmetry of the lower extremities was observed. Laboratory findings showed a significant increase in the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) after the gonadotropin-releasing hormone (GnRH) stimulation test; additionally, imaging demonstrated advanced bone age and pubertal changes in the internal genitals. Analyses of the H-RAS, K-RAS, and N-RAS genes in the blood and in the skin were performed, and a missense mutation in exon 2 of the gene, H-RAS c37G > C (p.G13R), was detected in the latter. Treatment with triptorelin, a GnRH analog, was initiated, and it gave good clinical response. Epidermal nevus syndrome has a wide and variable systemic involvement. Thus, it is important to consider the development of precocious puberty for a prompt diagnosis and to strategize a multidisciplinary approach from the beginning.

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Section: Discussionmentioning

confidence: 99%

Association of Central Precocious Puberty with a Rare Presentation of Schimmelpenning–Feuerstein–Mims Syndrome in a Peruvian Girl

Torre

Villar

Lama

et al. 2020

Case Reports in Endocrinology

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“…Frequently patients show extracutaneous manifestations such as neurological, skeletal, cardiac, ocular or metabolic features. 1,[5][6][7] Approximately 30 cases of PPK have been reported in the literature. Until recently, the aetiopathogenetic hypothesis proposed by Happle was widely accepted.…”

Section: Discussionmentioning

confidence: 99%

“…They argued that a single activating dominant HRAS mutation in heterozygosity was responsible for the appearance of both the cutaneous and extracutaneous manifestations of PPK. 3,10 However, this may not be completely accurate, because since that initial description five more cases of PPK with available genetic analysis have been reported, 4,6,7,11,12 two of them showing BRAF 4,12 and one showing KRAS mutation. 6 Nevertheless, as those alterations involve the Ras-Raf-MEK-ERK pathways, we can affirm that PPK is a mosaic RASopathy, as are SN and epidermal keratinocytic naevus or Schimmelpenning syndrome, among others.…”

Section: Discussionmentioning

confidence: 99%

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Phacomatosis pigmentokeratotica: a case of HRAS mosaicism causing rhabdomyosarcoma

et al. 2018

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A 17-year-old male presented with a large sebaceous naevus (SN) comprising part of his right face and scalp and a speckled lentiginous naevus (SLN) on his left trunk, hip, neck and scalp with a checkerboard pattern. His right oral hemimucosa showed extensive papillomatous lesions, which were contiguous with the upper-lip SN lesions. He also showed extracutaneous manifestations including cardiac, musculoskeletal and ocular alterations. Internally, he had developed two primary rhabdomyosarcomas. DNA samples of the SN, SLN, oral papillomatous hyperplasia and both rhabdomyosarcomas were analysed by Sanger sequencing. An HRAS c.37G>C mutation was detected in all of them. Skin and blood DNA were wild-type. Phacomatosis pigmentokeratotica (PPK) is characterized by the association of an SN with a papular naevus spilus and extracutaneous manifestations. Until recently, the aetiopathogenetic hypothesis of didymosis was accepted. However, in 2013 Groesser et al. proved the existence of an activating HRAS mutation as the cause of this syndrome. A higher incidence of cancer has been observed in germline RASopathies. Furthermore, up to 30% of human cancers show dysregulation of the Ras-Raf-MEK-ERK pathways. In our patient, an HRAS mosaic mutation explains not only the cutaneous but also the extracutaneous manifestations. To our knowledge this is the first described case of PPK in which the existence of an HRAS mosaic mutation is the confirmed cause of rhabdomyosarcoma. Furthermore, the HRAS c.37G>C mutation has never been related to any type of rhabdomyosarcoma. Mosaicisms could be underdiagnosed causes of childhood tumours. As dermatologists we stand in a privileged position of being able to detect these alterations.

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“…It has been suggested that severe brain damage and antiepileptic drugs probably affect neurotransmitter pathways involved in gonadotropin control and that the normal hypothalamic inhibition of gonadotropins may be lost (34). Limited data have also been reported for patients with RASopathies and CPP, such as our patients with cardio facio cutaneous syndrome (BRAF mutation) (19, 36) or epidermal nevus syndrome with HRAS gene mutation (37,38,39). Ras-Raf-mEK-ERK signaling is impaired in these cases, but the precise mechanism leading to CPP remains unknown.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

Wannes

Elmaleh‐Bergès

Simon

et al. 2018

European Journal of Endocrinology

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Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.

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Phacomatosis pigmentokeratotica and precocious puberty associated with HRAS mutation

Cited by 13 publications

References 7 publications

Association of Central Precocious Puberty with a Rare Presentation of Schimmelpenning–Feuerstein–Mims Syndrome in a Peruvian Girl

Association of Central Precocious Puberty with a Rare Presentation of Schimmelpenning–Feuerstein–Mims Syndrome in a Peruvian Girl

Phacomatosis pigmentokeratotica: a case of HRAS mosaicism causing rhabdomyosarcoma

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

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