Rare genotypic case of Noonan-like syndrome

Luiza Vitan¹, Adrian V Comanici¹²

¹Pediatric Endocrinology Department,CF2 Clinical Hospital
²Titu Maiorescu University
Bucharest, Romania
Abstract: Noonan-like syndrome with loose anagen hair (MIM #607721) caused by SHOC2 mutation (95%) is
considered by most to be an overlapping condition with unusual features (loose anagen hair); some consider it to be
a distinct condition, while others consider it to be classified as Noonan syndrome. The common denominator of
conditions is the dysregulation of the MAPK pathway through germline cell mutations that contain the genes encoding
RAS proteins. RAS proteins play an essential role in the regulation of the cell cycle, growth, differentiation, aging and
apoptosis.
Mutant SHOC2 undergoes aberrant N-myristoylation that results in constitutive membrane targeting. This is thought to
support RAF1-stimulated MAPK activation and nuclear targets initiate inappropriate cellular responses.
Predominant mutation: c.4A>G,p.Ser2Gly. Autosomal dominant transmission.
Case history May 2019 in CF2 Hospital Clinic
Birth: 2600g, 48 cm, 39 weeks, pelvic  Pick GH to Insulin = 8.82 ng/ml-glucose=32
presentation, normal neurologic mg/dl;
development by age stages and slow  IGF1= 218 ng/ml (96-545);
growth curve.  136 cm (- 2.47 SD), 33 kg, B2P2G2;
 Pick GH to Clonidine = 6.06 ng/ml;
Ultrasound- monitored pregnancy  BA (9 years) < CA (12.2 years);
with appropriate fetal growth; triple  No Somatropin treatment.
normal test.
On fetal morphology 22.01.2008:
bilateral choroid plexus cyst 6/7 mm
left and 8/6 mm right, undetectable
phalanx of finger V.

Mother height 150 cm; the same

mutation.
Centogene AG, Germany
Clinical
 clinodactyly finger V, short middle phalanx of the 5 th finger, lip (23.09.2020)
coalescence surgically resolved, high palate, dental agglomerations,  SHOC2, c.1582C>T p.
small lower jaw thick neck, lumbar hyperlordosis, thoracic (Pro528Ser),
hypertrichosis, mild skin hyperpigmentation, thin and slow growing causative for Noonan-like
hair, no cardiac anomalies, slightly hoarse voice, hyperactivity syndrome with loose anagen
behavior; -3,3 SD in 2015; TH BoneXpert= 152,5 +/-2,7 cm hair type 1 (uncertain
significance- class 3)
Discussion: 1. About 100 cases reported
2. Risk of malignancy: 2 cases of neuroblastoma, 1 case of myelofibrosis, 1 case of cutaneous T-cell
lymphoma (2022) (c.4A>G)
3. SHOC2 gene – ‘’Leucine rich repeat scaffold protein’’; cr 10q25; key role in cellular processes still under
study; new mutations described in recent years
4. Any child with stature deficiency with prenatal/ postnatal onset and with over- 2.5 SD associated with
subtle phenotypic abnormalities, MUST undergo complex investigations to determine the etiology of
hypostature.
Refferences:
1. Martin Zenker, Thomas Edouard- Noonan syndrome: improving recognition and diagnosis, BMJ Journals, 25 Aug 2022
2. Cordeddu V et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair., Nat
Genet, 2009, vol. 41
3. Laura MAZZANTI, Emanuela SCARANO– Orphanet, Last update: November 2020- Noonan syndrome-like disorder with loose anagen hair
4. Zhurkova N.V., Kazakova K.- L.O. Badalyan Neurological Journal, Vol 1, No 3 (2020) - Noonan-like syndrome with loose anagen hair: three clinical cases