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LEOPARD syndrome 3(LPRD3)

MedGen UID:
462321
Concept ID:
C3150971
Disease or Syndrome
Synonyms: BRAF-Related LEOPARD Syndrome; LPRD3
 
Gene (location): BRAF (7q34)
 
Monarch Initiative: MONDO:0013380
OMIM®: 613707

Disease characteristics

Excerpted from the GeneReview: Noonan Syndrome with Multiple Lentigines
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML. [from GeneReviews]
Authors:
Bruce D Gelb  |  Marco Tartaglia   view full author information

Additional description

From MedlinePlus Genetics
Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome) is a condition that affects many areas of the body. As the condition name suggests, Noonan syndrome with multiple lentigines is very similar to a condition called Noonan syndrome, and it can be difficult to tell the two disorders apart in early childhood. However, the features of these two conditions differ later in life. The characteristic features of Noonan syndrome with multiple lentigines include brown skin spots called lentigines that are similar to freckles, heart defects, widely spaced eyes (ocular hypertelorism), a sunken chest (pectus excavatum) or protruding chest (pectus carinatum), and short stature. These features vary, however, even among affected individuals in the same family. Not all individuals with Noonan syndrome with multiple lentigines have all the characteristic features of this condition.

The lentigines seen in Noonan syndrome with multiple lentigines typically first appear in mid-childhood, mostly on the face, neck, and upper body. Affected individuals may have thousands of small dark brown skin spots by the time they reach puberty. Unlike freckles, the appearance of lentigines has nothing to do with sun exposure. In addition to lentigines, people with this condition may have lighter brown skin spots called café-au-lait spots. Café-au-lait spots tend to develop before the lentigines, appearing within the first year of life in most affected people.

Of the people with Noonan syndrome with multiple lentigines who have heart defects, about 80 percent have hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood. The hypertrophic cardiomyopathy most often affects the lower left chamber of the heart (the left ventricle). Up to 20 percent of people with Noonan syndrome with multiple lentigines who have heart problems have a narrowing of the artery from the heart to the lungs (pulmonary stenosis).

Noonan syndrome with multiple lentigines is one of a group of related conditions collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome with multiple lentigines, the RASopathies include Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Legius syndrome.

People with Noonan syndrome with multiple lentigines can have a distinctive facial appearance. In addition to ocular hypertelorism, affected individuals may have droopy eyelids (ptosis), thick lips, and low-set ears. Affected individuals also usually have an abnormal appearance of the chest; they either have pectus excavatum or pectus carinatum.

At birth, people with Noonan syndrome with multiple lentigines are typically of normal weight and height, but in some, growth slows over time. This slow growth results in affected individuals being shorter than average, although less than half of people with Noonan syndrome with multiple lentigines have significantly short stature.

Other signs and symptoms of Noonan syndrome with multiple lentigines include hearing loss caused by abnormalities in the inner ear (sensorineural deafness), mild intellectual disability, and extra folds of skin on the back of the neck. Affected males often have genital abnormalities, which can include undescended testes (cryptorchidism) and a urethra that opens on the underside of the penis (hypospadias). These abnormalities may reduce the ability to have biological children (decreased fertility). Females with Noonan syndrome with multiple lentigines may have poorly developed ovaries and delayed puberty.  https://medlineplus.gov/genetics/condition/noonan-syndrome-with-multiple-lentigines

Clinical features

From HPO
Cubitus valgus
MedGen UID:
490152
Concept ID:
C0158465
Acquired Abnormality
Abnormal positioning in which the elbows are turned out.
Tetralogy of Fallot
MedGen UID:
21498
Concept ID:
C0039685
Congenital Abnormality
People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.\n\nEach of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.\n\nSome people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.\n\nAlthough babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.\n\nCritical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.
Abnormal aortic valve morphology
MedGen UID:
488999
Concept ID:
C3164445
Anatomical Abnormality
Any abnormality of the aortic valve.
Abnormal mitral valve morphology
MedGen UID:
871272
Concept ID:
C4025759
Anatomical Abnormality
Any structural anomaly of the mitral valve.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Shield chest
MedGen UID:
322348
Concept ID:
C1834124
Finding
A broad chest.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Low posterior hairline
MedGen UID:
383755
Concept ID:
C1855728
Finding
Hair on the neck extends more inferiorly than usual.
Palpebral thickening
MedGen UID:
1369577
Concept ID:
C4476868
Finding
An increased thickness of the eyelid not related to acute inflammation.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Multiple lentigines
MedGen UID:
272242
Concept ID:
C1328931
Disease or Syndrome
Presence of an unusually high number of lentigines (singular
Epidermal hyperkeratosis
MedGen UID:
338541
Concept ID:
C1848773
Finding
Numerous nevi
MedGen UID:
341508
Concept ID:
C1849677
Finding
Few cafe-au-lait spots
MedGen UID:
870435
Concept ID:
C4024881
Finding
The presence of two to five cafe-au-lait macules.
Wide intermamillary distance
MedGen UID:
473489
Concept ID:
C1827524
Finding
A larger than usual distance between the left and right nipple.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Professional guidelines

PubMed

Hernández-Martín A, Duat-Rodríguez A
Actas Dermosifiliogr 2016 Jul-Aug;107(6):454-64. Epub 2016 Mar 12 doi: 10.1016/j.ad.2016.01.004. PMID: 26979265
Chan W, Fang-tian D, Hua Z, You-xin C, Rong-ping D, Ke T
Chin Med Sci J 2011 Dec;26(4):231-6. doi: 10.1016/s1001-9294(12)60006-6. PMID: 22218051
Lodish MB, Stratakis CA
Fam Cancer 2011 Sep;10(3):481-90. doi: 10.1007/s10689-011-9446-x. PMID: 21538076Free PMC Article

Recent clinical studies

Etiology

Tajan M, Paccoud R, Branka S, Edouard T, Yart A
Endocr Rev 2018 Oct 1;39(5):676-700. doi: 10.1210/er.2017-00232. PMID: 29924299
Hernández-Porras I, Guerra C
Methods Mol Biol 2017;1487:379-408. doi: 10.1007/978-1-4939-6424-6_28. PMID: 27924582
Abdel-Naser MB, Zouboulis CC
Rev Endocr Metab Disord 2016 Sep;17(3):353-365. doi: 10.1007/s11154-016-9368-x. PMID: 27342409
Lehmann AR, McGibbon D, Stefanini M
Orphanet J Rare Dis 2011 Nov 1;6:70. doi: 10.1186/1750-1172-6-70. PMID: 22044607Free PMC Article
Sarkozy A, Digilio MC, Dallapiccola B
Orphanet J Rare Dis 2008 May 27;3:13. doi: 10.1186/1750-1172-3-13. PMID: 18505544Free PMC Article

Diagnosis

Monda E, Prosnitz A, Aiello R, Lioncino M, Norrish G, Caiazza M, Drago F, Beattie M, Tartaglia M, Russo MG, Colan SD, Calcagni G, Gelb BD, Kaski JP, Roberts AE, Limongelli G
Circ Genom Precis Med 2023 Aug;16(4):350-358. Epub 2023 May 18 doi: 10.1161/CIRCGEN.122.003861. PMID: 37199218
Chan W, Fang-tian D, Hua Z, You-xin C, Rong-ping D, Ke T
Chin Med Sci J 2011 Dec;26(4):231-6. doi: 10.1016/s1001-9294(12)60006-6. PMID: 22218051
Lehmann AR, McGibbon D, Stefanini M
Orphanet J Rare Dis 2011 Nov 1;6:70. doi: 10.1186/1750-1172-6-70. PMID: 22044607Free PMC Article
Porciello R, Divona L, Strano S, Carbone A, Calvieri C, Giustini S
Dermatol Online J 2008 Mar 15;14(3):7. PMID: 18627709
Sarkozy A, Digilio MC, Dallapiccola B
Orphanet J Rare Dis 2008 May 27;3:13. doi: 10.1186/1750-1172-3-13. PMID: 18505544Free PMC Article

Therapy

Kumar Menia N, Bansal R, Gupta V
Ocul Immunol Inflamm 2024 May;32(4):429-432. Epub 2023 Mar 10 doi: 10.1080/09273948.2023.2183222. PMID: 36897931
Cui H, Song L, Zhu C, Zhang C, Tang B, Wang S, Wu G, Zou Y, Huang X, Hui R, Wang S, Wang J
Orphanet J Rare Dis 2019 Nov 13;14(1):252. doi: 10.1186/s13023-019-1204-4. PMID: 31722741Free PMC Article
Bonetti M, Paardekooper Overman J, Tessadori F, Noël E, Bakkers J, den Hertog J
Development 2014 May;141(9):1961-70. Epub 2014 Apr 9 doi: 10.1242/dev.106310. PMID: 24718990
Savage MO, Padidela R, Kirk JM, Malaquias AC, Jorge AA
Pediatr Endocrinol Rev 2009 Jun;6 Suppl 4:523-8. PMID: 19550387
Uçar C, Calýskan U, Martini S, Heinritz W
J Pediatr Hematol Oncol 2006 Mar;28(3):123-5. doi: 10.1097/01.mph.0000199590.21797.0b. PMID: 16679933

Prognosis

Sallam K, Kodo K, Wu JC
Circ J 2014;78(4):784-94. Epub 2014 Mar 17 doi: 10.1253/circj.cj-14-0182. PMID: 24632794Free PMC Article
Sen-Chowdhry S, McKenna WJ
Cell Commun Adhes 2014 Feb;21(1):3-11. doi: 10.3109/15419061.2013.876415. PMID: 24460197
Lehmann AR, McGibbon D, Stefanini M
Orphanet J Rare Dis 2011 Nov 1;6:70. doi: 10.1186/1750-1172-6-70. PMID: 22044607Free PMC Article
Reinker KA, Stevenson DA, Tsung A
J Pediatr Orthop 2011 Jul-Aug;31(5):599-605. doi: 10.1097/BPO.0b013e318220396e. PMID: 21654472
Sarkozy A, Digilio MC, Dallapiccola B
Orphanet J Rare Dis 2008 May 27;3:13. doi: 10.1186/1750-1172-3-13. PMID: 18505544Free PMC Article

Clinical prediction guides

Monda E, Prosnitz A, Aiello R, Lioncino M, Norrish G, Caiazza M, Drago F, Beattie M, Tartaglia M, Russo MG, Colan SD, Calcagni G, Gelb BD, Kaski JP, Roberts AE, Limongelli G
Circ Genom Precis Med 2023 Aug;16(4):350-358. Epub 2023 May 18 doi: 10.1161/CIRCGEN.122.003861. PMID: 37199218
Hernández-Martín A, Duat-Rodríguez A
Actas Dermosifiliogr 2016 Jul-Aug;107(6):454-64. Epub 2016 Mar 12 doi: 10.1016/j.ad.2016.01.004. PMID: 26979265
Sallam K, Kodo K, Wu JC
Circ J 2014;78(4):784-94. Epub 2014 Mar 17 doi: 10.1253/circj.cj-14-0182. PMID: 24632794Free PMC Article
Krejci P
Mutat Res Rev Mutat Res 2014 Jan-Mar;759:40-8. Epub 2013 Dec 1 doi: 10.1016/j.mrrev.2013.11.001. PMID: 24295726
Porciello R, Divona L, Strano S, Carbone A, Calvieri C, Giustini S
Dermatol Online J 2008 Mar 15;14(3):7. PMID: 18627709

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