Short Stature, Optic Nerve Atrophy, And Pelger-Huet Anomaly


A number sign (#) is used with this entry because of evidence that short stature, optic nerve atrophy, and Pelger-Huet anomaly (SOPH syndrome) is caused by homozygous mutation in the NBAS gene (608025) on chromosome 2p24.


Among the Yakuts, an Asian population isolate that is located in the northeastern part of Siberia, Maksimova et al. (2010) ascertained a short stature syndrome involving autosomal recessive postnatal growth failure, small hands and feet, loss of visual acuity with abnormalities of color vision, abnormal nuclear shape in neutrophil granulocytes (Pelger-Huet anomaly; see 169400), and normal intelligence.

Clinical Features

In the linguistically and geographically isolated Yakut population of northeastern Siberia, previously studied for the presence of autosomal dominant and recessive as well as X-linked recessive genetic diseases (Nogovitsina et al., 1999; Tarskaia et al., 2003; Tarskaia et al., 2004), Maksimova et al. (2010) ascertained 34 Yakut patients, 22 female and 12 male, all of whom had postnatal growth failure, loose and senile skin with depressed turgor of tissue, micromelia, brachydactyly, and bilateral optic nerve atrophy with nonprogressive loss of visual acuity, associated with complete or incomplete achromatopsia (color blindness). In addition, all of the patients who underwent hematologic examination (22 patients from 21 families) had a high frequency of hypolobulation of granulocyte nuclei, characteristic of Pelger-Huet anomaly. Features seen in at least 28 (82%) of the 34 patients included a brachycephalic skull with hypoplasia of the frontal and parietal tubers and narrow forehead, long senile face with small features, small orbits, bilateral exophthalmos, hypoplastic cheekbones, straight nose with prominent glabella, long philtrum, thin lips, high voice with harsh timber, short neck, hypermobility of small joints, muscular hypotonia, and wide feet with high arch. Other commonly seen features included fine hair, facial asymmetry, thick and/or bushy eyebrows, epicanthus, sandal gap, and wide big toes. All but 1 of the patients had normal intellectual function. Maksimova et al. (2010) designated the phenotype 'SOPH syndrome,' for short stature, optic atrophy, and Pelger-Huet anomaly.


In 33 Yakut patients with SOPH syndrome, who were known to be negative for mutation in the CUL7 gene (609577), which can result in Yakut short stature syndrome (see 273750), Maksimova et al. (2010) performed genomewide homozygosity mapping followed by fine mapping that narrowed the critical interval to a 1.1-Mb segment between the dinucleotide polymorphic markers M1491 and M1599 on chromosome 2p24.3.

Molecular Genetics

In 33 Yakut patients from 30 families with short stature, optic nerve atrophy, and Pelger-Huet anomaly (SOPH syndrome) mapping to chromosome 2p24.3, Maksimova et al. (2010) analyzed 2 candidate genes and identified homozygosity for a missense mutation in the NBAS gene (R1914H; 608025.0001) that segregated with disease. None of 203 Yakut controls carried the mutation in homozygous state, and the mutation was not found in 100 Japanese controls. Because in cases of autosomal dominantly inherited Pelger-Huet anomaly (169400) caused by mutation in the LBR gene (600024), the amount of LBR quantitatively affects lobulation of neutrophilic nuclei, Maksimova et al. (2010) analyzed neutrophils from a patient with SOPH syndrome and a control, but found LBR expression to be comparable between the 2 individuals.