Improved growth velocity of a patient with Noonan‐like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low‐dose growth hormone therapy

Takasawa, Kei; Takishima, Shigeru; Morioka, Chikako; Nishioka, Masato; Ohashi, Hirofumi; Aoki, Yoko; Shimohira, Masayuki; Kashimada, Kenichi; Morio, Tomohiro

doi:10.1002/ajmg.a.37191

Cited by 5 publications

(4 citation statements)

References 20 publications

(29 reference statements)

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“…Generalized hyperpigmentation was noted in 15%, almost always in adult patients, and it appeared highly specific to PTPN11 ‐NSML in our study as it was always absent in other NS genotypes. These results were consistent with previous studies, except for SOS1 ‐NS and SHOC2 ‐NS, for which hyperpigmentation was noted for an average of 49% and 68% of cases, respectively . Our strict definition of generalized hyperpigmentation excluded localized or partial forms of hyperpigmentation, and the inclusion of patients with an ethnic origin conferring a familial medium or dark skin colour could explain these results.…”

Section: Discussionsupporting

confidence: 92%

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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Summary Background Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. Objectives To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype–genotype correlations with or without the presence of PTPN11 mutations. Methods We performed a large 4‐year, prospective, multicentric, collaborative dermatological and genetic study. Results Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11‐NS, 34 patients with PTPN11‐NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11‐NS, present in 53·8% of patients. Multiple lentigines and café‐au‐lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. Conclusions The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

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Section: Discussionsupporting

confidence: 92%

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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“…NS/LAH is an autosomal-dominant RASopathy characterized by features that resemble NS in previously published reports [ 3 – 11 ]. The key distinguishing features in NS/LAH encompass ectodermal anomalies, such as loose anagen hair (thin, easily pluckable hair), a hypernasal voice, and hyperpigmented skin [ 12 – 15 ].…”

Section: Discussionmentioning

confidence: 84%

“…It is essential for establishing and maintaining tissue homeostasis and balance in various tissues. The SHOC2 c.4A>G (p.Ser2Gly) variant is commonly seen in Noonan syndrome (NS; OMIM 163950) or Noonan-like syndrome with loose anagen hair (NS/ LAH; OMIM 607721) case reports [ 3 – 11 ]. NS/LAH is an auto-somal dominant RASopathy characterized by features that resemble NS [ 12 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant

Liu,

Hu,

Chen

et al. 2023

Am J Case Rep

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Patient: Female, 7-year-old Final Diagnosis: Noonan-like syndrome with loose anagen hair Symptoms: Thrombocytopaenia and anaemia Clinical Procedure: — Specialty: Genetics • Hematology • Pediatrics and Neonatology Objective: Rare disease Background: RASopathies involve mutations in genes that encode proteins participating in the RAS-mitogen-activated protein kinase pathway and are a collection of multisystem disorders that clinically overlap. Variants in the SHOC2 gene have been reported in Noonan-like syndrome, which include distinct facial features, short stature, congenital cardiac defects, developmental delays, bleeding disorders, and loose anagen hair. This report is of a 7-year-old girl with the c.4A>G (p.Ser2Gly) variant of the SHOC2 gene, consistent with Noonan-like syndrome, with loose anagen hair, presenting with thrombotic thrombocytopenic purpura and autoimmune hemolytic anemia. Case Report: The child had a medical history of 7 hospitalizations at our institution. At the age of 2 months, she underwent surgical correction for ventricular and atrial septal defects. At the age of 2 years, tonsil and adenoid removal surgery was performed, followed by surgery for otitis media at age 5 years. At 7 years, she was hospitalized for the simultaneous occurrence of thrombotic thrombocytopenic purpura and autoimmune hemolytic anemia. The patient displayed short stature and mild intellectual disability. Notable facial features included sparse hair, mild frontal bossing, and low-set ears. Antinuclear antibody levels demonstrated a significant gradual shift. Through trio whole-exome sequencing, a c.4A>G (p.Ser2Gly) variation in the SHOC2 gene was identified. Conclusions: Given the clinical information and genetic testing results, the patient’s condition appeared to closely be a type of RASopathy. This report has highlighted the importance of physical, developmental, and genetic testing in children presenting with dysmorphism, developmental delay, and hematological abnormalities.

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“…Severe short stature is frequently reported in SHOC2 Ser2Gly variant patients who exhibit mild to moderate GHD and growth hormone insensitivity (GHI) and thus require a higher dose of GH therapy (e.g., 35-40 μg/kg/day) (Cordeddu et al, 2009;Capalbo et al, 2012a;Capalbo et al, 2012b;Mazzanti et al, 2013). Whereas, a previously reported patient with Ser2Gly variant who had severe short stature was remarkably improved by low-dose GH therapy (25 μg/kg/day) (Takasawa et al, 2015). Currently, short stature was only described in two subjects with pathogenic variants (Met173Val and Gln269Arg respectively) other than Ser2Gly, in the recently published literature.…”

Section: Discussionmentioning

confidence: 99%

Case report: A de novo RASopathy-causing SHOC2 variant in a Chinese girl with noonan syndrome-like with loose anagen hair

Wang

Cheng

et al. 2022

Front. Genet.

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Pathogenic variants in the RASopathy-causing SHOC2 gene have been suggested to cause Noonan syndrome-like with loose anagen hair (NS/LAH). This condition is characterized by facial features resembling Noonan syndrome (NS), short stature, growth hormone deficiency (GHD), cognitive deficits, cardiac defects, and ectodermal abnormalities, including easily pluckable, sparse, thin, slow-growing hair, hyperpigmented skin and hypernasal voice. The mutation spectrum of SHOC2 is narrow, and only 8 pathogenic variants have been identified. Here, we report a 5-year-3-month-old Chinese female who displays characteristics typical of NS and has normal neurodevelopment. Trio-based whole-exome sequencing (WES) revealed a de novo variant (c.1231A>G, p.Thr411Ala) in SHOC2. This variant has been recently reported in one subject in the literature who displayed facial features typical of NS and also presented with significant speech delays, moderate intellectual disabilities, epilepsy, bilateral sensorineural deafness and renal dysplasia. The differential phenotypes between these subjects deserve to be further investigated. Next, we reviewed the clinical pictures of NS/LAH and noticed that a recurrent SHOC2 Ser2Gly variant was more likely to result in delayed neurodevelopment and short stature, compared to other SHOC2 variants. And growth hormone (GH) therapy could improve height prognosis. It was noticed that the slight sleep problems and friendly and relatively mature personality observed in our patient may be a novel phenotype of NS/LAH. Our study reconfirms the pathogenic nature of the SHOC2 Thr411Ala variant. It also provides insights into the genotype-phenotype relationship in NS/LAH and a foundation for its genetic counseling, diagnosis and treatment.

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Improved growth velocity of a patient with Noonan‐like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low‐dose growth hormone therapy

Cited by 5 publications

References 20 publications

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant

Case report: A de novo RASopathy-causing SHOC2 variant in a Chinese girl with noonan syndrome-like with loose anagen hair

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