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Café au Lait Macules and Associated Genetic Syndromes

      Abstract

      Café au lait macules (CALMs) are a common, isolated dermatologic finding in the general population. But when do these irregularly shaped, jagged-edged, flat, hyperpigmented birthmarks suggest something that may warrant referral? Most pediatric providers are familiar with the association of CALMs and neurofibromatosis type 1. There are, however, other genetic conditions associated with these seemingly benign skin spots. This article provides an overview of CALMs, followed by a summary of several conditions associated with CALMs ranging from the most common (neurofibromatosis type 1) to rare, ring chromosome syndromes. It reviews the associated gene(s), pattern of inheritance, incidence, presenting symptoms, diagnosis, and management for these genetic conditions.

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        Describe diagnostic criteria and/or testing for several genetic syndromes associated with café au lait macules.
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        Discuss appropriate surveillance and referral for individuals with café au lait macules.
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      Café au lait macules (CALMs) are hyperpigmented, flat skin lesions that arise from more active, pigment-producing melanocytes in the epidermis. They may be present at birth but may also grow in number and size over time. Most CALMs are benign and when identified, the greatest concern is often cosmetic. There are, however, several genetic syndromes associated with CALMs that should prompt referral. This article provides an overview of CALMs, followed by a summary of several diagnoses associated with these macules ranging from the most common, neurofibromatosis type 1 (NF 1), to less common ring chromosome syndromes. The associated gene(s), pattern of inheritance, incidence, presenting symptoms and findings, diagnosis, surveillance, and management for these conditions will be described.

      CAFÉ AU LAIT MACULES

      Flat, pigmented birth marks are typically described as café au lait (French for coffee with milk) spots or macules, but other names that appear in the literature include giraffe, coast of California, and coast of Maine spots. These lesions are light brown in color but can vary in pigment. These primary, de novo (new or spontaneous), irregularly shaped skin lesions can occur anywhere on the body but appear most frequently on the trunk and extremities and least commonly on the face. Some have smooth, well-defined borders and others have more-jagged edges (Figures 1 and 2). They arise from increased melanin production by melanocytes in the basal layer (stratum basale) of the epidermis. There is no increase in the number of melanocytes in the area; the dendritic pigment-producing cells are simply more active and thus manufacture more melanin, resulting in darker pigment (
      • Bohjanen K.
      Structure and functions of the skin.
      ). Café au lait macules can range in size from a few millimeters to several centimeters (>20 cm;
      • dos Santos A.C.E.
      • Heck B.
      • De Camargo B.
      • Vargas F.R.
      Prevalence of café-au-lait spots in children with solid tumors.
      ,
      • Fenyk J.
      Skin signs of systemic disease.
      ,
      • Shah K.N.
      The diagnostic and clinical significance of café-au-lait macules.
      ), and the size and shape of the macule have no greater or lesser significance or health implication.
      FIGURE 1
      FIGURE 1Coast of California café au lait macules. Smooth-bordered, homogeneously colored coast of California café au lait macules of varying size, shape, and shades of pigmentation on infants and children with dark and light skin tones. Sources: (A)
      • Purkait R.
      • Samanta T.
      • Thakur S.
      • Dhar S.
      Neurocutaneous syndrome: A prospective study.
      . (B)
      • Benelli E.
      • Belcaro C.
      • Ventura A.
      • Berti I.
      Legius syndrome: Case report and review of the literature.
      . (C, D)
      • Raus J.
      • Coroiu R.E.
      Albright syndrome-association of fibrous dysplasia, café-au-lait skin spots and hyperthyroidism-case report.
      .
      (This figure appears in color online at www.jpedhc.org.)
      FIGURE 2
      FIGURE 2Coast of Maine café au lait macules. Irregularly bordered café au lait macules that tend not to cross the midline are characteristic of McCune-Albright syndrome. Source:
      • Collins M.T.
      • Singer F.R.
      • Eugster E.
      McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia.
      .
      (This figure appears in color online at www.jpedhc.org.)
      Café au lait macules are common in children. Most are present at birth and are difficult to appreciate (Wood's lamp may improve visibility), or they may emerge in the first few months or years of life. They can increase in number and size (in proportion to growth) over time (
      • Morelli J.G.
      Skin. In Current diagnosis & treatment: Pediatrics.
      ). Incidence ranges are typically quoted as 5% among White individuals and 15% among individuals of African descent. More specifically, the incidence of one CALM ranges between 0.3% and 27%, depending on age and race/ethnicity (
      • dos Santos A.C.E.
      • Heck B.
      • De Camargo B.
      • Vargas F.R.
      Prevalence of café-au-lait spots in children with solid tumors.
      ,
      • Shah K.N.
      The diagnostic and clinical significance of café-au-lait macules.
      ,
      • Tekin M.
      • Bodurtha J.N.
      • Riccardi V.M.
      Café au lait spots: The pediatrician's perspective.
      ). In newborns, CALMs are seen in 0.3% of Whites and 18% of those who identify as Black. Among school-age children, rates increase to as high as 13% of Whites and 27% of Blacks (
      • Tekin M.
      • Bodurtha J.N.
      • Riccardi V.M.
      Café au lait spots: The pediatrician's perspective.
      ). Most individuals present with one or two CALMs, and 1% to 14% of the population have three or more (
      • Ben-Shachar S.
      • Dubov T.
      • Toledano-Alhadef H.
      • Mashiah J.
      • Sprecher E.
      • Constantini S.
      • Messiaen L.M.
      Predicting neurofibromatosis type 1 risk among children with isolated cafe-au-lait macules.
      ,
      • dos Santos A.C.E.
      • Heck B.
      • De Camargo B.
      • Vargas F.R.
      Prevalence of café-au-lait spots in children with solid tumors.
      ,
      • Shah K.N.
      The diagnostic and clinical significance of café-au-lait macules.
      ).
      Most CALMs are benign and of no clinical significance. However, there are associated genetic conditions, some of which carry increased predisposition to cancers (
      • dos Santos A.C.E.
      • Heck B.
      • De Camargo B.
      • Vargas F.R.
      Prevalence of café-au-lait spots in children with solid tumors.
      ) and/or other health problems. The condition associated with CALMs for which most providers are familiar is NF 1. Other syndromes associated with multiple CALMs include other RASopathies such as Legius syndrome, Watson syndrome, and Noonan syndrome with multiple lentigines, and others such as McCune–Albright syndrome, ring chromosome syndromes, and constitutional mismatch repair deficiency. An overview of each of the conditions for which the presence of CALMs may enter the differential diagnosis is discussed. Additionally, the genetics/inheritance, incidence, diagnostic criteria, diagnostic testing, and available treatments for these conditions are summarized to ensure that pediatric providers know when and why genetic referral is indicated.
      Most CALMs are benign and of no clinical significance.

      NEUROFIBROMATOSIS TYPE 1

      NF 1 is an autosomal dominant, multisystem condition caused by a change in the NF1 gene and, rarely (5%), a microdeletion located on the long arm of chromosome locus 17q11.2. This gene encodes neurofibromin, a protein that downregulates cellular proto-oncogenes and, as such, acts as a tumor suppressor. Variants in NF1 lead to production of nonfunctional neurofibromin that cannot regulate cell growth and division. Approximately 50% of individuals inherit the genetic change from a parent, and in the other half they occur sporadically (de novo). The condition has high penetrance and variability in the expression of clinical features. The incidence of NF 1 is 1 in 3,000 to 4,000 live births worldwide (
      • Johnson K.J.
      • Hussain I.
      • Williams K.
      • Santens R.
      • Mueller N.L.
      • Gutmann D.H.
      Development of an international internet-based neurofibromatosis type 1 patient registry.
      , ,
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      Neurofibromatosis type 1.
      ).
      Café au lait macules are the hallmark feature of NF 1, and multiple CALMs (≥6 greater than 5 mm) raises suspicion for the diagnosis. Other findings that evolve over time include axillary and inguinal skin-fold freckling, 1- to 3-mm pigmented macules resembling CALMs (Crowe's sign), usually by age 5 years; multiple cutaneous and subcutaneous neurofibromas that can form along the long peripheral nerves; iris Lisch nodules; and choroidal freckling. Plexiform neurofibromas occur in approximately 30% of individuals and are believed to be congenital, internal, and a significant cause of mortality among affected individuals (
      • Rosser T.
      Neurocutaneous disorders.
      ).
      It is unclear why learning disabilities are present in 30% to 70% of individuals with NF1. Overall, compared with their siblings, individuals with NF 1 have lower IQ scores but are not intellectually disabled (IQ < 70;
      • Payne J.M.
      • Moharis M.D.
      • Webster R.
      • North K.N.
      Brain structure and function in neurofibromatosis type 1: Current concepts and future directions.
      ). Some show behaviors consistent with attention deficit hyperactivity disorder and others, autism and social impairment (
      • Garg S.
      • Green J.
      • Leadbitter K.
      • Emsley R.
      • Lehtonen A.
      • Evans D.G.
      • Huson S.M.
      Neurofibromatosis type 1 and autism spectrum disorder.
      ).
      More serious problems that occur less frequently include optic nerve and other central nervous system gliomas (optic pathway gliomas and glioblastoma) and peripheral nerve sheath tumors (spinal neurofibromas, plexiform neurofibromas, and malignant nerve sheath tumors). Skeletal abnormalities include risk for scoliosis, sphenoid wing dysplasia, anterior chest wall deformities (pectus excavatum and pectus carinatum), and tibial dysplasia. Vasculopathies including renal stenosis, cerebral aneurysm, and risk for hemorrhagic and ischemic stroke also occur (
      • Gutmann D.H.
      • Ferner R.E.
      • Listernick R.H.
      • Korf B.R.
      • Wolters P.L.
      • Johnson K.J.
      Neurofibromatosis type 1.
      ,
      • Rosser T.
      Neurocutaneous disorders.
      ). The NIH diagnostic criteria for NF 1 is used to make a clinical diagnosis (Box 1). Although available, genetic testing is rarely needed to confirm a diagnosis of NF 1 and is typically reserved for children for whom there is high index of suspicion in the absence of diagnostic criteria or for whom a diagnosis of Legius syndrome is considered.
      NIH Diagnostic Criteria for NF 1 (1988)
      Clinical diagnosis is based on presence of two of the following:
        • Six or more café au lait macules over 5 mm in diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals
        • Two or more neurofibromas of any type or one plexiform neurofibroma
        • Freckling in the axillary or inguinal regions
        • Two or more Lisch nodules (iris hamartomas)
        • Optic glioma
        • A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
        • First-degree relative (parent, sibling, or offspring) with NF 1 by the above criteria
      Note. Recommendations to revise these criteria have been made to include the addition of other clinical features such as choroidal freckling, nevus anemicus, unidentified bright objects, and availability of molecular testing for NF 1 unknown at the time of the Consensus Conference (
      • Curless R.G.
      • Siatkowski M.
      • Glaser J.S.
      • Shatz N.J.
      MRI diagnosis of NF-1 in children without café-au-lait skin lesions.
      ,
      • Ferrari F.
      • Masurel A.
      • Olivier-Faivre L.
      • Vabres P.
      Juvenile xanthogranuloma and nevus anemicus in the diagnosis of neurofibromatosis type 1.
      ,
      • Parrozzani R.
      • Clementi M.
      • Frizziero L.
      • Miglionico G.
      • Perrini P.
      • Cavarzeran F.
      • Midena E.
      In vivo detection of choroidal abnormalities related to NF1: Feasibility and comparison with standard NIH diagnostic criteria in pediatric patients.
      ,
      • Tadini G.
      • Milani D.
      • Menni F.
      • Pezzani L.
      • Sabatini C.
      • Esposito S.
      Is it time to change the neurofibromatosis 1 diagnostic criteria?.
      ). Source:
      National Institutes of Health Consensus Development Conference
      Neurofibromatosis: Conference statement.
      .
      Children born into a family with affected individuals can usually be diagnosed by 1 year of age because the criteria of family history has been met when multiple CALMs are identified. For those without a family history, about half will meet diagnostic criteria by 1 year of age, and almost all meet criteria by age 8 years (
      • DeBella K.
      • Szudek J.
      • Friedman J.M.
      Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children.
      ). Pending presentation of a second symptom (typically axillary freckling and neurofibromas), children are typically followed by a geneticist or other skin specialist familiar with genetic CALM syndromes. Annual ophthalmology evaluations are recommended to screen for optic pathway glioma.
      Once a diagnosis of NF1 is confirmed, treatment rests with ongoing surveillance of growth and development, including pubertal changes and the presentation of ophthalmologic, skeletal, neurologic, cardiac, and endocrine findings, to ensure appropriate screening and timely specialist referral. There are published guidelines to guide longitudinal surveillance, the most recent of which was published in 2008 by the American Academy of Pediatrics Committee on Genetics (
      • Hersh J.H.
      American Academy of Pediatrics Committee on Genetics
      Health supervision for children with neurofibromatosis.
      ). Growth parameters including height, weight, and head circumference and pubertal development should be followed closely. Macrocephaly and hydrocephalus can be associated with tumor development, and delayed or precocious puberty may develop secondary to a pituitary hypothalamic lesion (
      • Ferner R.E.
      • Huson S.M.
      • Thomas N.
      • Moss C.
      • Willshaw H.
      • Evans D.G.
      • Kirby A.
      Guidelines for the diagnosis and management of individuals with neurofibromatosis 1.
      ). Blood pressure should be monitored to assess for secondary hypertension related to NF 1 vasculopathy (renal artery stenosis) and pheochromocytoma. Developmental assessments are important, as is referral to a neurologist should neurologic deficits be suspected. Individual educational and behavioral concerns must be addressed through school and supplemental services. Ophthalmologic evaluations including slit lamp examination are needed annually to age 8 years and less frequently in older children and adults. Skeletal surveillance includes monitoring for signs of tibial dysplasia and scoliosis. Tibial dysplasia (anterolateral bow) increases risk for fracture, tibial pseudoarthrosis, and limb length discrepancy. Dystrophic scoliosis is most common, but nondystrophic scoliosis can develop.
      Diagnostic studies such as magnetic resonance imaging (MRI) should be prescribed if there are clinical signs or symptoms that warrant further study. If malignant tumors are identified, surgical and medical oncologists familiar with molecular oncogenic mechanisms and inherent tumor predispositions should provide treatment. In addition, parents of children with a confirmed diagnosis of NF 1 should have skin and ophthalmologic examinations and genetic counseling to discuss inheritance, and recurrence risk should be provided.

      WATSON SYNDROME

      Watson syndrome (CALMs with pulmonary stenosis) is an autosomal dominant genetic disorder with clinical and molecular overlap with NF 1 and, thus, is considered a variant of NF 1. Individuals with a Watson syndrome phenotype appear to have nontruncating NF1 variants more frequently than the truncating variants found in other individuals with NF 1 (
      • Ben-Shachar S.
      • Constantini S.
      • Hallevi H.
      • Sach E.K.
      • Upadhyaya M.
      • Evans G.D.
      • Huson S.M.
      Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: A novel genotype-phenotype correlation.
      ).
      In addition to CALMs, Watson syndrome is characterized by pulmonic stenosis (52%), intellectual disability (68% with borderline or reduced intelligence), and short stature (80%), a key discriminating factor. Additionally, approximately one-half of patients have relative macrocephaly (absolute macrocephaly is seen in NF 1) and Lisch nodules (58%), and approximately one-third have neurofibromas (
      • Allanson E.
      • Upadhyaya M.
      • Watson G.H.
      • Partington M.
      • MacKenzie A.
      • Lahey D.
      • Huson S.M.
      Watson syndrome: Is it a subtype of type 1 neurofibromatosis?.
      ,
      Online Mendelian Inheritance in Man
      193520: Watson syndrome; WTSN.
      ). Affected individuals meet NIH diagnostic criteria for NF 1, but associated features of NF 1 and its complications are unusual (
      • Allanson E.
      • Upadhyaya M.
      • Watson G.H.
      • Partington M.
      • MacKenzie A.
      • Lahey D.
      • Huson S.M.
      Watson syndrome: Is it a subtype of type 1 neurofibromatosis?.
      ). Treatment rests with surveillance and management of patient-specific symptoms.

      LEGIUS SYNDROME

      Legius syndrome (NF 1–like syndrome) is an autosomal dominant syndrome characterized by multiple CALMs, axillary freckling, macrocephaly and, in some cases, Noonan syndrome facial features (Box 2). It is caused by pathogenic mutations in SPRED1, located on chromosome band 15q14, which provides instructions for making the Spred-1 protein that regulates the Ras/mitogen-activated protein kinase (MAPK) signaling pathway involved in cell proliferation, differentiation, cell movement, and apoptosis. It remains unclear how SPRED1 mutations cause the signs and symptoms associated with Legius syndrome (
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      SPRED1 gene.
      ). Because some affected individuals are likely misdiagnosed with NF 1 (5% meet NF 1 diagnostic criteria), the incidence for Legius syndrome is unknown (
      • Rosser T.
      Neurocutaneous disorders.
      ).
      Facial features suggestive of Noonan syndrome
      Hypertelorism
      Flat nasal bridge
      Downward slanting palpebral fissures
      Ptosis
      Low-set posteriorally rotated ears, thickened helices
      Thin lips
      Short/broad/webbed neck, redundant nuchal skin
      Sources:
      • Allanson J.E.
      • Roberts A.E.
      Noonan syndrome.
      ;
      U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
      Ring chromosome 17.
      .
      Although some individuals meet clinical diagnostic criteria for NF 1, over time those with Legius syndrome do not develop other symptoms consistent with NF 1 such as Lisch nodules, optic pathway gliomas, neurofibromas, tibial dysplasia, or central nervous system tumors, which differentiates these two conditions later in life (
      • Friedman J.M.
      Neurofibromatosis 1.
      ). Most have average intelligence levels, but some individuals with Legius syndrome have learning disabilities, attention deficit disorder, or attention deficit hyperactivity disorder (
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      Legius syndrome.
      ). Learning problems in children with Legius syndrome are less severe than in those with NF 1 (
      • Denayer E.
      • Chrmara M.
      • Breams H.
      • Kievit A.M.
      • van Bever Y.
      • Van den Ouweland A.M.W.
      • Legius E.
      Legius syndrome in fourteen families.
      ). Physical examination of the parent may help differentiate between NF 1 and Legius syndromes, but in sporadic cases, ongoing evaluation and molecular testing may be required to confirm the diagnosis (
      • Friedman J.M.
      Neurofibromatosis 1.
      ).
      Management through childhood replicates that of NF1. To differentiate between NF1 and Legius syndrome in prepubertal individuals with multiple CALMs and intertriginous freckling when the diagnosis remains unclear, genetic testing can be performed. Those with a confirmed diagnosis of Legius syndrome do not require brain and spine MRI or ophthalmologic examinations like those with NF 1.

      NOONAN SYNDROME WITH MULTIPLE LENTIGINES

      Noonan syndrome with multiple lentigines (formerly referred to as LEOPARD syndrome) is an autosomal dominant RASopathy that presents with CALMs that are often dark brown (café noir macules) coupled with lentigines (Figure 3) characterized by irregular borders, small size (<0.5 cm), and carrying shades of brown and black. The incidence of the condition is unknown, and to date, approximately 200 cases have been reported worldwide (
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      Noonan syndrome with multiple lentigines.
      ). This genetic condition is caused by a pathogenic variant in one of four genes (BRAF, MAP2K1, PTPN11, and RAF1;
      • Friedman J.M.
      Neurofibromatosis 1.
      ), and genetic testing to confirm the diagnosis is recommended.
      FIGURE 3
      FIGURE 3Skin findings consistent with Noonan syndrome with multiple lentigines. (A) Characteristic jagged-edged, coast of Maine café au lait macule on the upper left chest. With careful inspection, multiple faintly, colored lentigines are visible, consistent with Noonan syndrome with multiple lentigines. (B, C) In addition to café au lait and café noir macules (French for black coffee), multiple lentigines are consistent with Noonan syndrome with multiple lentigines. Sources: (A)
      • Santoro C.
      • Pacileo G.
      • Limongelli G.
      • Scianguetta S.
      • Giugliano T.
      • Piluso G.
      • Perrotta S.
      LEOPARD syndrome: Clinical dilemmas in differential diagnosis of RASopathies.
      . (B, C)
      • Sarkozy A.
      • Digilio M.C.
      • Dallapiccola B.
      Leopard syndrome.
      .
      (This figure appears in color online at www.jpedhc.org.)
      In addition to multiple lentigines and facial features similar to Noonan syndrome (Box 2), other findings of Noonan syndrome with multiple lentigines include pulmonic stenosis; abnormal genitalia; growth retardation (25%); sensorineural deafness (25%); and skeletal conditions including pectus carinatum and excavatum, scoliosis, scapular winging, syndactyly, and joint hypermobility. Approximately 30% of affected individuals have learning difficulties, but intellectual disability is rare (
      • Rosser T.
      Neurocutaneous disorders.
      ).
      Those with a confirmed or suspected diagnosis require cardiac surveillance including echocardiogram, to assess for cardiac problems such as pulmonic stenosis and hypertrophic cardiomyopathy, and electrocardiogram, to monitor for arrhythmias such as right bundle branch block and other conduction abnormalities. Growth, learning, and hearing (annually) must also be closely monitored and problems addressed as needed (
      • Rosser T.
      Neurocutaneous disorders.
      ).

      MCCUNE–ALBRIGHT SYNDROME

      McCune–Albright syndrome is a rare genetic condition with an estimated prevalence of 1 in 100,000 to 1,000,000 individuals worldwide (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ,
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      McCune-Albright syndrome.
      ). It is not inherited but, rather, results from a pathogenic mutation in the GNAS gene during early embryonic postzygotic development that results in mosaicism. The presentation and severity of the condition is highly variable and depends on the number and distribution of affected cells with the changed gene (

      U.S. Department of Health and Human Services, National Center for Biotechnology Information, U.S. National Library of Medicine, Genetic Testing Registry. (n.d.). McCune-Albright syndrome. Bethesda, MD: Author. Retrieved fromhttps://www.ncbi.nlm.nih.gov/gtr/conditions/C0242292/

      ,
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      McCune-Albright syndrome.
      ) ranging from asymptomatic to incidental findings to neonatal lethality (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ). Café au lait macules appear at birth or shortly thereafter and are typically irregularly bordered (Coast of Maine) and appear unilaterally after embryonic cell migration along the lines of Blaschko (Figure 2). Its classical presentation is a triad of CALMs, fibrous dysplasia of the bone, and precocious puberty, but over time, several endocrinopathies have also been recognized.
      Although McCune–Albright syndrome is typically identified through dermatologic findings, this condition also affects the skeleton and endocrine tissues. Fibrous dysplasia, a condition in which bone is replaced with fibrous tissue, typically manifests the first few years of life and predisposes affected individuals to fractures, uneven growth, and resulting deformity. Any bones in the body may be affected. The extent of disease may range from an isolated finding (monostotic lesion) to severe, polyostotic disease of the entire skeleton, appearing in a mosaic pattern similar to the skin. There is no association between the size of the CALMs, extent of disease, or location of fibrous dysplasia (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ). Skull and facial bone lesions can cause asymmetric facial growth and deformity; uneven long bone growth can result in gait disturbances, limping, and loss of mobility; and asymmetric growth of vertebrae can result in scoliosis. The skull and proximal femurs are most commonly affected.
      Although McCune–Albright syndrome is typically identified through dermatologic findings, this condition also affects the skeleton and endocrine tissues.
      Endocrine problems associated with McCune–Albright syndrome occur in both females and males and include precocious puberty and hyperthyroidism. The presentation of precocious puberty in females is highly variable and unpredictable. Girls may present with gonadotropin-independent precocious puberty caused by recurrent estrogen-producing ovarian cysts, vaginal bleeding as young 2 years of age, breast tissue development, and enhanced growth and bone age (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ,
      • Corica D.
      • Aversa T.
      • Pepe G.
      • De Luca F.
      • Wasniewska M.
      Peculiarities of precocious puberty in boys and girls with McCune-Albright syndrome.
      ). Biochemical findings include high estradiol levels and diminished gonadotropins. Although rare in males, signs of precocious puberty result from autonomous testosterone production and include macroorchidism with or without signs of sexual precocity. Testicular lesions in the presence or absence of gonadotropin-independent precocious puberty may occur (
      • Corica D.
      • Aversa T.
      • Pepe G.
      • De Luca F.
      • Wasniewska M.
      Peculiarities of precocious puberty in boys and girls with McCune-Albright syndrome.
      ).
      Individuals develop thyroid lesions with or without autoimmune hyperthyroidism, and there is also risk for growth hormone excess, which may lead to acromegaly and coarse facial features. Of note, enhanced growth hormone increases the effects of polyostotic fibrous dysplasia. Fibroblast growth factor 23 (FGF23)–mediated phosphate wasting with or without hypophosphatemia can also be present, exacerbating the effect of fibrous dysplasia. Infrequently, the adrenal glands can be affected, resulting in neonatal hypercortisolism (Cushing syndrome), typically before age 2 years (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ,
      • Dean L.
      McCune-Albright syndrome.
      ).
      Although genetic testing for McCune–Albright syndrome is available, the mosaic nature of the disease makes traditional leukocyte testing less than ideal. For example, in those with only monostatic fibrous dysplasia, targeted molecular testing (sequencing of GNAS exons 8 and 9) of the affected tissue is necessary to identify a pathogenic variant in GNAS with a sensitivity of 80% in lesional tissue compared with 20% to 30% in peripheral blood lymphocytes (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ). Although no formal diagnostic criteria have been established, most individuals with McCune–Albright syndrome receive a clinical diagnosis based on the presence of two or more physical findings.
      Individualized management rests with clinical presentation, meticulous surveillance, and a multidisciplinary approach to treatment to optimize function and minimize morbidity. Surveillance by an endocrinologist includes close monitoring of infants for signs of hypercortisolism. This is followed by monitoring growth and growth acceleration (bone age), assessing for signs of precocious puberty, and initiating medical treatment as indicated. Males must be followed for testicular lesions on physical examination and ultrasonography, and females require more stringent breast cancer screening. Children younger than 5 years of age require close monitoring for thyroid abnormalities including periodic ultrasonography and thyroid function studies. Treatment may include thyroidectomy (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ).
      Skeletal surveillance includes monitoring for progressive scoliosis and radiographs to identify and monitor new lesions of fibrous dysplasia. Phosphorus and 25-hydroxyvitamin D levels should be followed. Those with craniofacial fibrous dysplasia require annual vision and hearing screening, periodic computerized tomography scan of the skull, and serum insulin-like growth factor 1 levels through adolescence (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ).
      The prognosis for individuals with McCune–Albright syndrome depends on the location, extent, and severity of cell distribution (
      • Boyce A.M.
      • Florenzano P.
      • de Castro L.F.
      • Collins M.T.
      Fibrous dysplasia/McCune-Albright syndrome.
      ,
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      McCune-Albright syndrome.
      ). Of note, upper gastrointestinal polyps are now considered a common finding (
      • Wood L.D.
      • Noë M.
      • Hackeng W.
      • Brosens L.A.
      • Bhaijee F.
      • Debeljak M.
      • Montgomery E.A.
      Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas.
      ), and appropriate surveillance should be provided. Because McCune–Albright syndrome is caused by a de novo mutation that takes place after conception, there is no increased risk versus the general population the parents of an affected child to have another child with this condition. If the affected individual has the mutation in his/her sperm or eggs, each cell would inherit this change, making the embryo nonviable. In the absence of this, the condition is not passed to the offspring of affected individuals.

      RING CHROMOSOME SYNDROMES

      Ring chromosomes are aberrant chromosomes that occur when genetic material on the telomeres on both ends of a chromosome is lost, allowing the ends to stick together, forming a ring. Although extremely rare, ring chromosomes have been identified in all human chromosomes. They can be inherited, but most are sporadic (99%). The larger the chromosome, the more unstable it is. Symptoms result not from formation of the ring itself but, rather, the location and degree of telomeric deletion and lost genetic material when the ring is formed. Patient phenotype varies depending on these factors. The most uniform feature of ring chromosomes syndromes is marked growth delay (
      • Yip M.
      Autosomal ring chromosomes in human genetic disorders.
      ).
      Hyperpigmentation and CALMs are rare in individuals with ring chromosomes, but multiple CALMs have been reported in individuals with ring chromosome syndrome involving chromosomes 7, 11, 12, 15, and 17 (
      • Fagan K.
      • Suthers G.H.
      • Hardacre G.
      Ring chromosome 11 and café-au-lait spots.
      ,
      U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
      Ring chromosome 15.
      ,
      U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
      Ring chromosome 7.
      ,
      U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
      Ring chromosome 12.
      ,
      U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
      Noonan syndrome.
      ; ). More specifically, 30% of individuals with deletion of distal chromosome arm 15q secondary to a ring chromosome have CALMs (
      • Morava E.
      • Bartsch O.
      • Czako M.
      • Frensel A.
      • Kárteszi J.
      • Kosztolányi G.Y.
      A girl with cutaneous hyperpigmentation, café au lait spots and ring chromosome 15 without significant deletion.
      ), and in addition to CALMs, ring chromosome 7 is also associated with nevus flammeus and dark pigmented nevi (
      • Lange R.
      • Von Linsingen C.
      • Mata F.
      • Moraes A.B.
      • Arruda M.
      • Neto L.V.
      Endocrine abnormalities in ring chromosome 11: A case report and review of the literature.
      ). Individuals with CALMs associated with ring chromosome abnormalities may also have patchy hypopigmented areas suggestive of cytogenetic mosaicism (Figure 4b). Karyotype will confirm the diagnosis, and treatment rests with symptom- and condition-specific management.
      FIGURE 4
      FIGURE 4Dermatologic findings consistent with constitutional mismatch repair deficiency syndrome. (A) Café au lait macules of varying size and pigment in a child with constitutional mismatch repair deficiency syndrome. (B) Also note the area of hypopigmentation. Source:
      • Lavione N.
      • Colas C.
      • Muleris M.
      • Bodo S.
      • Duval A.
      • Entz-Werle N.
      • Briegeres L.
      Constitutional mismatch repair deficiency syndrome: Clinical description in a French cohort.
      .
      (This figure appears in color online at www.jpedhc.org.)

      CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY

      Constitutional mismatch repair (MMR) deficiency (CMMRD) is an autosomal recessive condition that results from pathogenic variants in MMR genes (MLH1, MSH2 [including methylation due to an EPCAM deletion], MSH6, and PMS2) associated with Lynch syndrome (Box 3;
      • Wimmer K.
      • Kratz C.P.
      • Vasen H.F.A.
      • Colas C.
      • Entz-Werle N.
      • Gerdes A.M.
      EU-Consortium Care for CMMRD
      Diagnostic criteria for constitutional mismatch repair deficiency syndrome: Suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD).
      ). Typically, individuals with germline MLH1 or MSH2 defects develop MMR-deficient cancers in their 40s to 50s, and those with MSH6 or PMS2 mutations are affected less consistently. Individuals with biallelic germline mutations in MMR genes, however, have CMMRD (
      • Bodo S.
      • Colas C.
      • Buhard O.
      • Collura A.
      • Tinat J.
      • Lavoine N.
      • Duval A.
      Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents.
      ).
      Lynch syndrome
      Lynch syndrome (also called hereditary non-polyposis colorectal cancer) is an autosomal dominant cancer predisposition syndrome. Heterozygous (monoallelic) germline mutations in mismatch repair genes MLH1, MSH2 (including methylation due to an EPCAM deletion), MSH6 and PMS2 increase the risk of developing Lynch syndrome. The most common mutations are MSH1 and MLH2, which account for approximately 90% of mutations, but not all who inherit the changed gene will develop cancer. Inheriting one of these genetic changes, however, increases the lifetime risk cancer, especially colorectal (40%–82%) and stomach (1%–13%), as well as gastrointestinal tract (small intestine, pancreas, liver, gallbladder ducts), upper urinary tract, brain (glioblastomas), and skin cancers (keratoacanthomas and sebaceous adenomas). For women, there is increased risk of ovarian (4%–12%) and endometrial (25%–60%) cancers. Lifetime cancer risk is lower for individuals with MSH6 and PMS2 mutations. There are several published diagnostic criteria such as the Amsterdam criteria and/or Bethesda guidelines, but they are limited in their sensitivity. A multigene panel that includes MLH1, MSH2, MSH6, PMS2, and EPCAM deletion, along with other genes of interest, is recommended to establish a diagnosis.
      References:
      • Aarnio M.
      • Sankila R.
      • Pukkala E.
      • Salovaara R.
      • Aaltonen L.A.
      • de la Chapelle A.
      • Järvinen H.J.
      Cancer risk in mutation carriers of DNA-mismatch-repair genes.
      ;
      • Carethers J.M.
      • Stoffel E.M.
      Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer.
      ;
      • Kohlmann W.
      • Gruber S.B.
      Lynch syndrome.
      .
      Although areas of skin hypopigmentation have been reported, most individuals with CMMRD present with CALMs (Figure 4). The clinical presentation is variable and may include skinfold freckling, Lisch nodules, neurofibromas, and tibial pseudarthrosis, making differentiation between NF 1 and CMMRD difficult (
      • Hampel H.
      • Bennett R.L.
      • Buchanan A.
      • Pearlman R.
      • Wiesner G.L.
      A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: Referral indications for cancer predisposition assessment.
      ). There is phenotypic overlap with other cancer syndromes, and there are no equivocal diagnostic features of CMMRD. Thus, this syndrome is likely to go unrecognized by clinicians, and subsequently, its incidence underreported (
      • Bodo S.
      • Colas C.
      • Buhard O.
      • Collura A.
      • Tinat J.
      • Lavoine N.
      • Duval A.
      Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents.
      ). There are reports suggesting that CALMs associated with CMMRD vary in pigmentation, have irregular borders, and may display a segmental distribution not characteristic of NF 1 (
      • Wimmer K.
      • Kratz C.P.
      • Vasen H.F.A.
      • Colas C.
      • Entz-Werle N.
      • Gerdes A.M.
      EU-Consortium Care for CMMRD
      Diagnostic criteria for constitutional mismatch repair deficiency syndrome: Suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD).
      ).
      In contrast to NF 1, individuals with CMMRD develop childhood cancers, including Lynch syndrome-associated cancers (colorectal tumors and multiple intestinal polyps), hematologic malignancies, brain/central nervous system tumors, and embryonic tumors and rhabdomyosarcoma different than those with NF 1 (
      Online Mendelian Inheritance in Man
      276300: Mismatch repair cancer syndrome; MMRCS.
      ). Additionally, most parents of children with CMMRD are consanguineous. One or both parents may have no clinical findings of NF 1, but there may be a family history (first- or second-degree relatives) of Lynch syndrome (
      • Bodo S.
      • Colas C.
      • Buhard O.
      • Collura A.
      • Tinat J.
      • Lavoine N.
      • Duval A.
      Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents.
      ,
      • Friedman J.M.
      Neurofibromatosis 1.
      ). This rate is low, and individuals with CMMRD do not always have a family history of cancer (
      • Bodo S.
      • Colas C.
      • Buhard O.
      • Collura A.
      • Tinat J.
      • Lavoine N.
      • Duval A.
      Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents.
      ,
      • Hampel H.
      • Bennett R.L.
      • Buchanan A.
      • Pearlman R.
      • Wiesner G.L.
      A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: Referral indications for cancer predisposition assessment.
      ).
      Even though causative genes for CMMRD are known, genetic screening is not informative for 30% of patients for whom testing shows variants of uncertain significance. Additionally, testing for PMS2 (responsible for 60% of CMMRD) is complicated by pseudogenes, which results in a lack of sensitivity with mutation analysis only. Therefore, although mutation testing for CMMRD is possible, it is far from straightforward (
      • Bodo S.
      • Colas C.
      • Buhard O.
      • Collura A.
      • Tinat J.
      • Lavoine N.
      • Duval A.
      Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents.
      ).
      Because of the increased risk for neoplasia and early-age onset of cancers, treatment rests with meticulous tumor screening to ensure early detection and treatment to improve patient outcome. Although there are no established standardized screening criteria, proposed guidelines published in 2017 recommend the following surveillance: (a) cranial ultrasound at 6 months of age until the fontanel is closed, followed by brain MRI every 6 months starting at 2 years; (b) complete blood count every 6 months beginning at 1 year of age; (c) colonoscopy annually beginning at age 6 years; (d) upper endoscopy and video capsule endoscopy annually beginning at 8 years; (e) urinalysis annually beginning at age 10 years; and (f) for women, pelvic examination with endometrial sampling annually beginning at age 20 years. Total body MRI has been suggested for screening, but the recommendation regarding this remains uncertain (
      • Durno C.
      • Boland R.
      • Cohen S.
      • Dominitz J.A.
      • Giardiello F.M.
      • Johnson D.A.
      • Rex D.K.
      Recommendations on surveillance and management of biallelic mismatch repair deficiency (BMMRD) syndrome: A consensus statement by the US Multi-Society Task Force on Colorectal Cancer.
      ).

      FAMILIAL CAFÉ AU LAIT MACULES

      Familial cafe au lait macules or spots (CALSs), multiple CALSs, CALS syndrome, or NF type 6 are names used to describe the autosomal dominant inheritance of CALMs. The diagnosis of this condition is typically made when a first-degree relative has similar physical findings and no other stigmata or clinical manifestations of NF 1. Overall, 80% to 99% of individuals with familial CALMs have more than 6 CALMs, ranging from a few millimeters to greater than 10 cm, and in about 5% to 29%, there is skin fold freckling (
      U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
      Autosomal dominant café au lait spots.
      ,
      • Madson J.G.
      Multiple or familial café-au-lait spots is neurofibromatosis type 6: Clarification of a diagnosis.
      ,
      Online Mendelian Inheritance in Man
      114030: Cafe-au-lait spots, multiple.
      ). Individuals with familial CALMs have none of the other physical findings consistent with NF 1 (neurofibromas or Lisch nodules), and this remains a diagnosis of exclusion because findings of NF1 evolve over time.

      CONCLUSION

      There is no question that CALMs are generally benign hyperpigmented skin lesions, and although they may be of no specific clinical significance, they may be the hallmark for a genetic disorder. Subtle differences in the characteristics of CALMs, coupled with the presentation of other physical and developmental findings, helps differentiate genetic conditions associated with CALMs. As providers, it is imperative that we examine the skin thoroughly at least annually, and when a CALM is identified, it should prompt the provider to look for the presence of others and count and record the finding. Based on the child's age, number of CALMs, family history, and presence of any other clinical findings suggestive of genetic disease, the provider must establish a plan for ongoing surveillance or referral.
      Subtle differences in the characteristics of CALMs, coupled with the presentation of other physical and developmental findings, helps differentiate genetic conditions associated with CALMs.

      Appendix. Supplementary materials

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        Autosomal dominant café au lait spots.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
        Ring chromosome 7.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
        Ring chromosome 12.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center
        Ring chromosome 17.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
        Legius syndrome.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
        McCune-Albright syndrome.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
        Neurofibromatosis type 1.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
        Noonan syndrome.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
        Noonan syndrome with multiple lentigines.
        Author, Bethesda, MD2018 (Retrieved from)
        • U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference
        SPRED1 gene.
        Author, Bethesda, MD2019 (Retrieved from)
        • Wimmer K.
        • Kratz C.P.
        • Vasen H.F.A.
        • Colas C.
        • Entz-Werle N.
        • Gerdes A.M.
        • EU-Consortium Care for CMMRD
        Diagnostic criteria for constitutional mismatch repair deficiency syndrome: Suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD).
        Medical Genetics. 2014; 51: 355-365
        • Wood L.D.
        • Noë M.
        • Hackeng W.
        • Brosens L.A.
        • Bhaijee F.
        • Debeljak M.
        • Montgomery E.A.
        Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas.
        Virchows Archiv. 2017; 470: 391-400
        • Yip M.
        Autosomal ring chromosomes in human genetic disorders.
        Translational Pediatrics. 2015; 4: 164-174

      Biography

      Sharon Anderson, Associate Professor and Assistant Dean, Division of Advanced Nursing Practice, Rutgers School of Nursing, Newark, NJ; and Advanced Practice Nurse, Rutgers Robert Wood Johnson Medical Pediatric Genetics, Child Health Institute of New Jersey, New Brunswick, NJ.