Noonan syndrome differential diagnosis
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Noonan syndrome can be considered in any patient with congenital cardiac anomalies although 3 important syndromes can resemble the Noonan phenotype particularly LEOPARD syndrome, Costello syndrome, and Turner syndrome in girls.
LEOPARD syndrome, also known as multiple lentigines syndrome, is a rare congenital condition characterized by skin, facial and cardiac anomalies. LEOPARD is an acronym that summarizes the most important features of this disease which includes Lentigines, ECG findings (conduction abnormalities), Ocular problems (hypertelorism), Pulmonic stenosis, Abnormal genitalia, growth Retardation, and Deafness. Phenotypically and genotypically, LEOPARD syndrome closely resembles Noonan syndrome although around 200 cases have only been reported worldwide. The disorder also involves mutations in the PTPN11 gene responsible for the NSH-2 domain on SHP-2. Several common loci of missense mutations are shared between these 2 syndromes, and genetic analysis alone can sometimes be hard to differentiate the two. Clinically, LS is a combination of neurofibromatosis type 1 and Noonan syndrome. The lentigines are important to make the diagnosis, although some do not appear before 4 to 5 years of age. Other signs more prominent in LS compared to Noonan are the very high prevalence of hypertrophic cardiomyopathy and deafness.
Costello syndrome is an autosomal dominant disorder that occurs secondary to germline mutations in the HRAS proto-oncogene that is characterized by growth retardation, coarse facial features, loose skin, cardiomyopathy, developmental delay and friendly behavior. Patients with Costello syndrome usually develop oral papillomata and are at a higher predisposition for malignancy especially rhabdomyosarcoma. The pathophysiology is unclear, but recent studies suggest defects in elastogenesis.
Turner syndrome is a congenital disorder that occurs in 1 of every 2000 to 5000 live female births. It does not affect male patients as it is characterized by an XO karyotype. Clinically, Turner syndrome can have variable phenotypes with features usually including congenital lymphedema, short stature, congentical cardiac abnormalities, and gonadal dysgenesis. Although Turner syndrome has been genetically and clinically delineated and can be differentiated from Noonan's syndrome, initially, Noonan's was considered a form of Turner syndrome that can affect males due to the marked overlap between the 2 disorders. In 1968, Dr. Jacqueline Noonan published a paper entitled "Hypertelorism With Turner Phenotype: A New Syndrome With Associated Congenital Heart Disease" describing the syndrome as "the male Turner syndrome". In females with any difficulty in differentiating the syndromes clinically due to the variable expression, karyotype and genetic analysis are helpful.
It is absolute that delayed puberty is the result of any disturbances in hypothalamus-pituitary-gonadal (HPG) axis. Delayed puberty has found to be on a genetic basis, most of the times. It is assumed that the main factor in determining the puberty timing is genetic elements. In case of constitutional delay of growth and puberty (CDGP), researchers suggested 50-75% of positive family history of delayed puberty. About 25 various genes, in 3 different group of Kallman syndrome related genes, hypothalamus-pituitary-gonadal (HPG) axis related genes, and obesity related genes, play roles in delayed puberty. Boys are more commonly affected by delayed puberty (constitutional delay of puberty) than girls. The most potent risk factor in the development of delayed puberty is hypothalamus-pituitary-gonadal (HPG) axis disturbance. Other risk factors are including genetic, endocrinologic, and environmental; which may disturb the HPG axis. Patients with delayed puberty usually appear normal, not ill or toxic. Physical examination of patients with delayed puberty is usually remarkable for delayed growth spurt along with small testicular size (less than 4 mL or 2.5 cm) in more than 14 years old boys and thelarche stage 0-1 in more than 13 years old girls.
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