RASopathies: Dermatologists’ viewpoints

Genotype-phenotype variations

Genotype-phenotype variations in neurofibromatosis type 1 are mostly related to severity and results from deletions. A mild phenotype [Figure 3] with café au lait macules but few or without cutaneous neurofibromas, plexiform neurofibromas and optic pathway glioma occur with 3-bp microdeletion (p.Met⁹⁹2del,exon 17) of NF1.^18,37-41 However, these phenotypes suffer from significant cognitive impairment, learning disabilities and non-optic pathway gliomas.⁴¹ A rare missense mutation of Arg¹⁸⁰⁹ also present without neurofibromas, but café au lait macules and Lisch nodules are present. This phenotype is similar to Noonan syndrome with post-natal developmental delay, learning disability and pulmonary stenosis.⁴¹

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Figure 3:

Mild phenotype of neurofibromatosis type 1 in an adult with few café au lait macules and countable cutaneous neurofibroma

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Large 17q11.2 microdeletion encompassing full NF1 and the flanking genes (5–10% cases) results in the most severe phenotype with early-onset cutaneous neurofibroma, subcutaneous and spinal neurofibromas, dysmorphic face, tall for age stature with large hands and feet, hyper-flexible joints, low intelligence, muscle hypotonia, increased cardiovascular anomalies and most importantly high risk (16–26%) of malignant peripheral nerve sheath tumours^18,38,42 Severe phenotype is also associated with missense mutation of codons 844–848.^39,41

Diagnosis of neurofibromatosis type 1 in adolescents and adults is easier because of “tell-tale” clinical picture, but confirmation is based on available diagnostic criteria.⁴³ All clinical features of neurofibromatosis type 1 are not manifest since birth when one or more café au lait macules are the only findings. Chronology of the appearance of important clinical features of neurofibromatosis type 1 is presented in Table 4.^32,34-36,44 Some cutaneous lesions such as juvenile xanthogranuloma, nevus anemicus and glomus tumor are under consideration for inclusion in diagnostic criteria as these appear earlier.³⁶

Malignancy is the frequent cause of death and malignant peripheral nerve sheath tumors are the most common.¹⁸ These are highly aggressive spindle cell sarcomas (life-time risk 8–13%). Subtle indicators of malignant conversion in an internal neurofibroma or existing plexiform neurofibomas include unexplained pain, rapid growth, change in texture and newly developed neuro-deficit.^18,36

Genotype-phenotype variations

More than 10 various gene mutations may result in Noonan syndrome phenotype; PTPN11 is the most common followed by RAF1 and SOS1 mutations.^4,17 There is significantly higher frequency of keratinization and hair disorders, generalized hyperpigmentation (adults) and pulmonary stenosis in patients with PTPN11 mutation, but minimal or no intellectual impairment^17,23 RAF1 mutation is associated with macrocephaly,¹⁹ significant intellectual impairment (95%),^17,19 hypertrophic cardiomyopathy,¹⁷ laryngomalacia and hoarse cry during infancy.⁹ Patients with SOS1 have hypertelorism and ptosis consistently,⁴⁵ and mild or no cognitive impairment.¹⁷ Patients with CBL mutation are susceptible to develop myeloproliferative disorders, including juvenile myelomonocytic leukemia and those with KRAS mutations may have severe phenotype similar to Cardio-Facio-Cutaneous syndrome.¹⁷

Clinical features

The clinical picture is dominated by short stature, age-wise variable facial features and congenital heart disease.²⁰ Post-natal growth retardation is common and the height of the affected children is less than 3^rd percentile.^1,20-22 In adulthood 85% of the affected individuals continue to have stunted growth.^1,20,21 Various morphological features of Noonan syndrome are presented in Table 5.^{1,4,10,20-22,44,45}

Cutaneous manifestations

Patients with classic Noonan syndrome may have subtle cutaneous manifestations. Adult patients have thin, transparent and lax skin. Low posterior hair line [Figure 4b], palmo-plantar hyperkeratosis, café au lait macules, lentigines and nevi (approximately 10% of patients with KRAS mutations) are present.^20-22 In a recent prospective, multicentric study among 129 confirmed Noonan syndrome patients, it was observed that multiple lentigines, > 3 café au lait macules, significantly higher keratinization and hair disorders, such as keratosis pilaris, ulerythema ophryogenes, sparse scalp hair and sparse or absent eyelashes are more consistently associated with PTPN11 mutations.²²

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Figure 4a:

Widely-spaced nipples in a boy with suspected Noonan syndrome

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Figure 4b:

Low posterior hair line in the same boy as in Figure 4a

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Ocular manifestations

In a retrospective study among a large cohort of patients with Noonan syndrome, ocular abnormalities were frequent.⁴⁵ Permanent visual impairment due to refractive errors and optic nerve anomalies were commoner with RAF1, SHOC2 and KRAS, but not seen in patients with PTPN11 mutations.⁴⁵ Other visual abnormalities recorded were proptosis, strabismus, nystagmus, prominent corneal nerves and keratoconus.⁴⁵

Systemic involvement

Congenital heart disease is present in more than 80% patients.²⁰ The classical cardiac lesion is pulmonary stenosis, others being atrial septal defect, ostium secundum type and peripheral pulmonary arterial stenosis.^1,20 These cardiovascular anomalies are more frequent with PTPN11 mutation.²⁰ Feeding difficulties in childhood, reflux, vomiting, cognitive dysfunction, poor language development, difficulties in spelling and reading may be present.^20,21

Haematological findings

Patients with Noonan syndrome frequently present with bleeding tendency and easy bruising.^20,22 A diverse haematological abnormalities have been found (30–72%).¹⁷ Factor XI deficiency, von Willebrand disease and quantitative and/or functional disorder of platelets are most frequently described.¹⁷

Associated malignancies

Approximately 10% Noonan syndrome may have mild bone marrow abnormalities.²⁰ Various malignancies are seen in 4% patients, with peak during childhood.¹¹ These patients are predisposed to various leukemia such as juvenile myelomonocytic leukemia and acute myelomonocytic leukemia.^1,4,11,20 Solid organ tumors described are low grade glioma, neuroblastoma and embryonal rhabdomyosarcoma.^11,20

In adults clinical suspicion of Noonan syndrome may be delayed because of subtle facial appearance.¹ However, as Noonan syndrome is a common cause of congenital heart disease world-wide, it should be ruled out in all such patients presented at any age.²⁰ In doubtful cases, checking the childhood photograph of the patient and parents may be helpful.²⁰ Clinical and laboratory evaluation for bleeding disorders (coagulation disorder profile and platelet count) must be done at diagnosis and thereafter before any surgical intervention.¹⁷

There are indicators of fetal Noonan syndrome during pregnancy. These include polyhydramnios, fetal complications such as edema, pleural effusion and hydronephrosis.²⁰ Pre-natal diagnosis is possible in suspected cases or in the presence of positive family history. Gestational ultrasonography may be done at 12–14 weeks, 20 weeks and third trimester.²⁰ Increased nuchal skin fold, congenital heart disease, enlarged jugular lymphatic sac and cystic hygroma are some of the clinical indicators.²⁰ Fetal echocardiography may be done at 18–20 weeks for screening of congenital heart disease.²⁰Genetic analysis of the collected samples (fetal blood, chorionic villi and amniotic fluid) is confirmative.²⁰

Noonan syndrome with multiple lentigines (OMIM 1511000)

The earlier nomenclature of Noonan syndrome with multiple lentigines was LEOPARD Syndrome, (Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth and following Deafness) syndrome.^46,47 Specific missense mutation of PTPN11 or RAF1 constitutes an allelic disorder,²³ the second frequent following Noonan syndrome.⁴⁷

Facial and other structural anomalies are grossly similar to Noonan syndrome.²³ Hypertelorism is a consistent feature (100%) [Figure 5].⁴⁷

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Figure 5:

Hypertelorism in a boy with suspected Noonan syndrome with multiple lentigines

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Cutaneous features include multiple café au lait macules (>3 in 80% cases) and lentigines. café au lait macules are present since early infancy, typically darker, linear or rhomboid in shape with irregular, ragged borders [Figure 6a] in contrast to the light brown, round or oval café au lait macules of Neurofibromatosis type 1.^22,23 The hallmark lentigines start appearing by five to six years of age, increase in number to more than 1000 during puberty and darken during adulthood.²³ These are typically black [Figure 6b], mostly spread over the face [Figure 7] and upper trunk with accentuation on axillary and inguinal folds, palms and soles, usually sparing the mucous membranes.²³ Extremities, genitalia, lips and conjunctiva may also be involved with lentigines. Café noir spots are darkly pigmented skin lesions usually ranging from 2 mm to more than 5 cm in size. Histopathologically, these may represent melanocytic nevi with or without dysplastic features or lentigo simplex.⁴⁸ Nevus spilus-like lesions and multiple melanocytic nevi, more than 2 mm in diameter and more than 50 in number may be present.²³

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Figure 6a:

Suspected case of Noonan syndrome with multiple lentigines, dark brown rhomboid cafe au lait macules with ragged border and cafe noir spots on the right of abdomen

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Figure 6b:

Typical black coloured lentigines in the same patient as Figure 6a

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Figure 7:

Lentigines aggregated on face and lips with small pointed chin in a case of suspected Noonan syndrome with multiple lentigines

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Left ventricular hypertrophic cardiomyopathy is more commoner (80% of the cardiac anomalies) than pulmonary stenosis in Noonan syndrome with multiple lentigines.^17,23,47 Hypertrophic cardiomyopathy may be present at birth well before the appearance of skin lesions, symptoms arise over the years and may lead to life-threatening sequelae.⁴⁷ Conduction abnormalities may be present in 75% cases detectable by electrocardiography.⁴⁷ Sensorineural deafness may be a feature in 15–25% affected children warranting specialised care and annual evaluation.⁴⁷

Noonan syndrome with multiple lentigines due to NRAS mutation, lack lentigines on face and neck; cardiac, ocular and hearing abnormalities are absent.²³ Facial features are milder with macroglossia. Webbing of neck is not a common finding.⁴⁴

Noonan syndrome with loose anagen hair syndrome (OMIM 607721)

Single missense mutation of SHOC2 presents with the rare phenotype Noonan syndrome with loose anagen hair.²²

Frequent cutaneous findings include multiple hair anomalies such as curly or wavy, sparse and slow-growing scalp hair.^22,49 The anagen follicles lack internal and external root sheath resulting in easily pluckable hair.⁹ However, hair morphology may alter with increasing age and may be of less diagnostic value. Temporal alopecia may be present.^20,22 Thin or absent eyelashes are a frequent feature.⁴⁹ Keratosis pilaris may be present.^1,20 Low-birth weight (<3^rd centile) and feeding difficulties are also reported.⁹

Cutaneous findings

Cutaneous markers of Costello syndrome have been well delineated in a cross-sectional study with 46 genetically proved cases.² Distinct morphological and cutaneous features of Costello syndrome are presented in Table 6.^{1,2,4,9,44,48}

Systemic features

Systemic features predominate the clinical picture in Costello syndrome leading to failure to thrive. These include severe feeding difficulty, poor suckling, reflux, hoarse voice and constipation since infancy.^4,14 The affected individuals require continuous medical aid by nasogastric intubation or gastrostomy.^4,14 Hypertrophic cardiomyopathy is the most common congenital heart disease. There is high frequency (10–20%) of childhood malignancies, the most common being embryonal rhabdomyosarcoma and neuroblastoma. Adolescents are prone to develop transitional cell carcinoma of urinary bladder.^1,4,28 Mild to moderate intellectual disabilities are common but the affected children grow with pleasant and sociable personality beyond infancy.^1,14

The combination of cutaneous papillomas, stippled pachydermatoglyphia and acanthosis nigricans in these patients are similar to that of acquired paraneoplastic syndromes.² Cutaneous papillomas and cosmetic disfigurement due to facial lesions are often the reason for dermatology consultation during childhood.² These are often misdiagnosed as viral warts and the underlying condition may be overlooked; re-appearance of the lesions after adequate removal is the pointer to an alternate diagnosis.