We report a child presenting with pigmentary skin lesions and spinal neurofibromas who was diagnosed molecularly with KRAS mosaicism. We review the previous literature of two cases of congenital skin lesions and neurofibromas and spinal nerve root hypertrophy caused by KRAS variants and highlight this presentation as an important differential diagnosis for neurofibromatosis.

Many RASopathies can be clinically diagnosed based on their cutaneous findings, thus it is essential for dermatologists to be comfortable differentiating RASopathies for accurate diagnosis and appropriate management. Employing the same framework to categorize as in Part I, the most common RASopathies include those principally caused by genetic variants in tumor suppressor genes (neurofibromatosis type 1, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome), those principally due to variants in oncogenes (Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome), and mosaic conditions such as sebaceous nevus syndrome, neurocutaneous melanosis, McCune-Albright syndrome, phakomatosis pigmentokeratotica, epidermal nevus syndrome, and encephalocraniocutaneous lipomatosis. Germline variants cause systemic disease and must be managed in conjunction with a multidisciplinary team of specialists for holistic care. Common extracutaneous manifestations affect the neurologic, psychiatric, cardiac, ocular, musculoskeletal, genitourinary, and hematologic systems. The genetic basis of disease necessitates family counseling with a geneticist and patient support groups. It is also important to recognize risk of cancer in RASopathy patients for appropriate surveillance. Thus, dermatologists play a critical role in patients' healthcare through familiarity with and prompt diagnosis of RASopathies.

RASopathies are common developmental disorders caused by variants in RAS and RAS-related proteins that affect a biological signaling pathway regulating cell growth and development. Considering the genetic and biochemical basis, part I will discuss the RASopathies divided into germline and mosaic patterns. The germline RASopathies include neurofibromatosis type 1 (not discussed in detail in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. Mosaic RASopathies encompass a broad category including nevus sebaceus syndrome, neurocutaneous melanosis, melanocytic nevi, McCune-Albright syndrome, phacomatosis spilosebacea, epidermal nevus syndrome, and encephalocraniocutaneous lipomatosis. Due to the RAS pathway's downstream impact on cell growth, many RASopathies predispose to malignancy. Conversely, the RAS pathway is overactive in many cancers, and some oncologic therapies also benefit patients with RASopathies. Although RAS ubiquity and homology complicate the efficacy of direct inhibition, several candidate drugs carry potential for decreasing RAS activity. Continued investigation into RAS biochemistry and genetics may elucidate strategies for pharmacological targets and pathways in both RASopathies and cancers. Nevus sebaceus of Jadassohn also referred to as organoid nevus, is a congenital malformation described in 1895 by the dermatologist Josef Jadassohn. These congenital malformations are hamartomas of the pilosebaceous follicular unit. These growths most commonly form on the scalp, but may also appear on the forehead, face, or neck. They undergo a growth phase during puberty due to hormonal changes in the patient's body. In adulthood, the growths may develop secondary neoplasms within them, most commonly trichoblastoma. The treatment of these lesions is controversial, with options ranging from observation to early excision in childhood. Features of the nevus sebaceus syndrome (also known as Schimmelpenning Feuerstein Mims syndrome) include a large or disseminated nevus sebaceus along with abnormalities of the central nervous, skeletal, or ocular systems. A rare condition known as phakomatosis pigmentokeratotica (PPK) is a subclassification of the epidermal nevus syndrome, in which a patient exhibits both a nevus sebaceus and at least one speckled lentiginous nevus.

Mosaicism results from postzygotic alterations during embryogenesis leading to genetically distinct populations of cells within individuals and has been historically recognized by phenotypes with visible, often patterned manifestations. Before the advent of molecular profiling assays and high-throughput sequencing, it was challenging to study mosaicism in human disease; however, the study of mosaic disorders has recently revealed unexpected and novel pathways for disease pathogenesis. In this paper, we will review the techniques for discovery of disease-causing alleles using Proteus syndrome; phakomatosis pigmentokeratotica; linear porokeratosis; and vacuoles, E1 enzyme, X-linked, autoinflammatory somatic syndrome as models. These tools represent powerful approaches for dissecting the genetic basis for human disorders.

Keratinocytic epidermal nevi (KEN) are characterized clinically by permanent hyperkeratosis in the distribution of Blaschko's lines and histologically by hyperplasia of epidermal keratinocytes. KEN with underlying RAS mutations have been associated with hypophosphatemic rickets and dysplastic bone lesions described as congenital cutaneous skeletal hypophosphatemia syndrome. Here, we describe two patients with keratinocytic epidermal nevi, in one associated with a papular nevus spilus, who presented with distinct localized congenital fibro-osseous lesions in the lower leg, diagnosed on both radiology and histology as osteofibrous dysplasia, in the absence of hypophosphatemia or rickets, or significantly raised FGF23 levels but with distinct mosaic HRAS mutations. This expands the spectrum of cutaneous/skeletal mosaic RASopathies and alerts clinicians to the importance of evaluating for bony disease even in the absence of bone profile abnormalities.