Alternative titles; symbols
ORPHA: 648; DO: 0060580;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.21 | Noonan syndrome 2 | 605275 | Autosomal recessive | 3 | LZTR1 | 600574 |
A number sign (#) is used with this entry because of evidence that Noonan syndrome-2 (NS2) is caused by homozygous or compound heterozygous mutation in the LZTR1 gene (600574) on chromosome 22q11.
Noonan syndrome (NS) is a multiple congenital anomalies syndrome characterized by a typical face, congenital heart disease, and short stature (summary by van der Burgt and Brunner, 2000).
For a general phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Johnston et al. (2018) reported 23 patients (21 of whom underwent molecular analysis) from 12 families with autosomal recessive Noonan syndrome. Birth length and birth head circumference was average to large for all children. Nine of 14 patients in whom it was evaluated had developmental delay. Sixteen of 19 had congenital heart defect or valve disease. Variable facial features of Noonan syndrome were reported in all, with 13 of 16 having low-set ears and 16 of 19 having a broad, short neck. Leukemia was reported in 2 families. Several patients presented prenatally with polyhydramnios, cystic hygroma, and/or arthrogryposis. Several patients died in the neonatal period. Cryptorchidism was rarely reported.
Van der Burgt and Brunner (2000) described 4 Dutch Noonan syndrome patients, 2 male and 2 female, each with unaffected consanguineous parents. All 4 had a typical Noonan syndrome phenotype and presented with hypertrophic obstructive cardiomyopathy at birth. In 2 patients the defect improved, in 1 patient it deteriorated, and in 1 patient it remained constant over 12 years. These patients supported the existence of an autosomal recessive form of Noonan syndrome in which hypertrophic obstructive cardiomyopathy is more frequent than in autosomal dominant Noonan syndrome.
Umeki et al. (2019) reported a patient with Noonan syndrome 2. In addition to distinctive facial features suggestive of Noonan syndrome, she had hypertrophic cardiomyopathy, 5th brachymetapody, and mild intellectual disability.
Abdel-Salam and Temtamy (1969) reported 2 sibs with Noonan syndrome from a first-cousin marriage. A deceased female sib may have been affected also. They suggested autosomal recessive inheritance.
Maximilian et al. (1992) reported a family with 4 children, of whom 3, a girl and 2 boys, were thought to have Noonan syndrome. Neither parent had signs of the syndrome.
Van der Burgt and Brunner (2000) reported 4 unrelated Dutch patients with Noonan syndrome who were born of unaffected consanguineous parents, suggesting autosomal recessive inheritance.
The transmission pattern of Noonan syndrome in the families reported by Johnston et al. (2018) was consistent with autosomal recessive inheritance.
Johnston et al. (2018) reported 17 mutations in 12 families with autosomal recessive Noonan Syndrome. These included missense, nonsense, frameshift, and splice site mutations that occurred in homozygosity or compound heterozygosity. All parents were heterozygous and unaffected.
Umeki et al. (2019) reported 1 NS2 patient with compound heterozygous mutations in the LZTR1 gene and 6 NS10 patients with heterozygous mutations in LZTR1. All patients had cardiac defects and 71% had hypertrophic cardiomyopathy. Other features were more variable. The patient with NS2 inherited each mutation from one of her unaffected parents.
Abdel-Salam, E., Temtamy, S. A. Familial Turner phenotype. J. Pediat. 74: 67-72, 1969. [PubMed: 5782826] [Full Text: https://doi.org/10.1016/s0022-3476(69)80009-0]
Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet. Med. 20: 1175-1185, 2018. [PubMed: 29469822] [Full Text: https://doi.org/10.1038/gim.2017.249]
Maximilian, C., Ioan, D. M., Fryns, J. P. A syndrome of mental retardation, short stature, craniofacial anomalie with palpebral ptosis and pulmonary stenosis in three siblings with normal parents: an example of autosomal recessive inheritance of the Noonan phenotype? Genet. Counsel. 3: 115-118, 1992. [PubMed: 1642809]
Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum. Genet. 138: 21-35, 2019. [PubMed: 30368668] [Full Text: https://doi.org/10.1007/s00439-018-1951-7]
van der Burgt, I., Brunner, H. Genetic heterogeneity in Noonan syndrome: evidence for an autosomal recessive form. Am. J. Med. Genet. 94: 46-51, 2000. [PubMed: 10982482] [Full Text: https://doi.org/10.1002/1096-8628(20000904)94:1<46::aid-ajmg10>3.0.co;2-i]