Growth and hormone profiling in children with congenital melanocytic naevi

Abstract

SummaryBackgroundMultiple congenital melanocytic naevi (CMN) is a rare mosaic RASopathy, caused by postzygotic activating mutations in NRAS. Growth and hormonal disturbances are described in germline RASopathies, but growth and hormone status have not previously been investigated in individuals with CMN.ObjectivesTo explore premature thelarche, undescended testes, and a clinically abnormal fat distribution with CMN through prospective endocrinological assessment of a cohort of subjects with CMN, and a retrospective review of longitudinal growth of a larger group of patients with CMN from outpatient clinics (which included all subjects in the endocrinological assessment group).Patients and methodsLongitudinal growth in a cohort of 202 patients with single or multiple CMN was compared with the U.K. National Child Measurement Programme 2010. Forty‐seven children had hormonal profiling including measurement of circulating luteinizing hormone, follicle‐stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin, pro‐opiomelanocortin, estradiol, testosterone, cortisol, thyroxine, insulin‐like growth factor‐1 and leptin; 10 had oral glucose tolerance testing 25 had dual‐energy X‐ray absorptiometry scans for body composition.ResultsBody mass index increased markedly with age (coefficient 0·119, SE 0·016 standard deviation scores per year), at twice the rate of the U.K. population, due to increased adiposity. Three per cent of girls had premature thelarche variant and 6% of boys had persistent undescended testes. Both fat and muscle mass were reduced in areas underlying large naevi, resulting in limb asymmetry and abnormal truncal fat distribution. Anterior pituitary hormone profiling revealed subtle and variable abnormalities. Oral glucose tolerance tests revealed moderate–severe insulin insensitivity in five of 10, and impaired glucose tolerance in one.ConclusionsInterpersonal variation may reflect the mosaic nature of this disease and patients should be considered individually. Postnatal weight gain is potentially related to the underlying genetic defect; however, environmental reasons cannot be excluded. Naevus‐related reduction of fat and muscle mass suggests local hormonal or metabolic effects on development or growth of adjacent tissues, or mosaic involvement of these tissues at the genetic level. Premature thelarche and undescended testes should be looked for, and investigated, as for any child.

Final congenital melanocytic naevi colour is determined by normal skin colour and unaltered by superficial removal techniques: a longitudinal study

“…Inclusion criteria were children with a diagnosis of CMN, where NRAS , BRAF or MC1R genotype was available, and where at least one set of professional in‐house hospital photographs was available. Extensive data on phenotype were collected using two separate classifications, the most recently proposed classification from 2013, and an in‐house classification used over the past 25 years and previously published . Final colour was defined as the latest measurement available for each patient.…”

Does the gene matter? Genotype–phenotype and genotype–outcome associations in congenital melanocytic naevi

“…Small single CMN are very common birthmarks, present in approximately 1% of all neonates, are not associated with extracutaneous abnormalities, and have a very low risk of transformation to melanoma . At the other end of the spectrum, multiple CMN (defined as two or more melanocytic naevi at birth) can cover up to 80% of the body surface area, can be associated with serious extracutaneous abnormalities, such as congenital neurological disease, typical facial features, underdevelopment of fat and muscle in naevoid areas, and endocrinological disturbance . The risk of melanoma in childhood varies with the congenital phenotype (both cutaneous and neurological), between 1% and 12% in prospective studies .…”

Malignant melanoma arising in congenital melanocytic nevi: clinical and dermoscopic challenges

“…Multiple CMN may reflect a mosaic RASopathy as a result of postzygotic activating mutations in NRAS [7], and patients with small CMN have a higher risk of MM. The lifetime risk of developing MM is estimated to be 1 in 100 for patients with small and medium CMN [8].…”