Alternative titles; symbols
SNOMEDCT: 1172898008; ORPHA: 477831;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q32 | Kosaki overgrowth syndrome | 616592 | Autosomal dominant | 3 | PDGFRB | 173410 |
A number sign (#) is used with this entry because of evidence that Kosaki overgrowth syndrome (KOGS) is caused by heterozygous mutation in the PDGFRB gene (173410) on chromosome 5q32.
Kosaki overgrowth syndrome (KOGS) is characterized by a facial gestalt involving prominent forehead, proptosis, downslanting palpebral fissures, broad nasal bridge, thin upper lip, and pointed chin. Affected individuals are tall, with an elongated lower segment, and have large hands and feet. Skin is hyperelastic and fragile. Patients exhibit progressive dilatory and vascular changes in basilar/vertebral and coronary arteries starting in the teenage years (Takenouchi et al., 2015; Takenouchi et al., 2021).
Takenouchi et al. (2015) described 2 unrelated Japanese girls with an overgrowth syndrome who exhibited strikingly similar facial features as well as hyperelastic, fragile skin, scoliosis, white matter lesions, and neurologic deterioration. The first girl had normal psychomotor development in childhood but exhibited accelerated linear growth. At age 8 years, she developed a 3-cm mandibular tumor that was removed surgically; pathology was consistent with myofibroma. At age 14, her height, lower-segment, hand, and foot length were all more than +4 SD. Facial features included prominent forehead and supraorbital ridge, mild proptosis, ptosis, downslanting palpebral fissures, broad nasal bridge, high columella insertion, thin upper lip, and pointed chin. Her skin was hyperelastic, thin, and fragile. In early adolescence, she began to have recurrent episodes of depression and anxiety as well as schizophrenic symptoms, including auditory hallucinations. The second girl, who had been reported by Watanabe et al. (2011) under a presumptive diagnosis of Shprintzen-Goldberg syndrome (see 182212) but who was negative for mutation in the SKI gene (164780), had normal psychomotor development in infancy and Stanford-Binet IQ of 73 at age 6 years, but her IQ was measured at less than 40 at age 13. She had distinctive facial features that were strikingly similar to those of the first girl, with a prominent forehead, proptosis, downslanting palpebral fissures, xanthoma on bilateral upper eyelids, broad and depressed nasal bridge, thin upper lip, and pointed chin. Both girls had thoracolumbar scoliosis, and both also exhibited an abnormal cranial shape with protrusion of the posterior fossa and a diffuse granular pattern on x-ray. Brain MRI showed extensive periventricular white matter lesions in both patients, but there was no evidence of intracranial calcification on CT scan. Family history was noncontributory in both cases.
Minatogawa et al. (2017) reported 2 unrelated females, aged 3 (patient 1) and 15 (patient 2) years, with KOGS. Both patients had accelerated growth in childhood (height +2.3 SD in patient 1 and +3.8 SD in patient 2) and scoliosis; patient 2 also had decreasing body mass index with age. Both patients also had impaired intellectual development, hyperplastic and fragile skin, and cerebral white matter changes on MRI. Patient 2 had long fingers and toes above the 97th percentile and patient 1 had constriction bands of the second and third fingers; neither patient had contractures. Both patients had hypertelorism and thinning of the upper part of the nasal ridge.
Gawlinski et al. (2018) described a 10-year-old boy with KOGS who had many characteristic features, including typical facies, overgrowth, and tall stature. The authors noted that he had additional features, including some that were not seen in infancy, but appeared later in life, suggesting a need to expand the phenotype. These included pronounced macrocephaly at birth and camptodactyly with worsening joint contractures beginning at age 6 years. In addition, the patient had scoliosis, a condition seen in 3 of the 4 previously reported patients, but the scoliosis was of earlier onset (age 4 years) than previously seen, and was rapidly worsening, even following surgical intervention. The patient had a sharp decrease in rate of development of height and weight beginning at age 6 years, possibly related to the surgical intervention on his spine. He also developed premature aging and lipodystrophy beginning at the age of 8 years, which had previously been seen in one patient with KOGS. At the age of 10 years, the patient had not developed psychiatric manifestations, myofibroma, or progressive neurologic deterioration.
The heterozygous mutations in the PDGFRB gene that were identified in Japanese patients with Kosaki overgrowth syndrome by Takenouchi et al. (2015) occurred de novo.
In a Japanese girl with overgrowth, facial dysmorphism, hyperelastic fragile skin, scoliosis, and neurologic deterioration, who was negative for mutation in 6 known overgrowth-associated genes, Takenouchi et al. (2015) performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in the PDGFRB gene (P584R; 173410.0005). Sequencing of the PDGFRB gene in an unrelated but similarly affected Japanese girl revealed heterozygosity for the same de novo mutation.
In 2 unrelated females with KOGS, Minatogawa et al. (2017) identified the same heterozygous missense mutation in the PDGFRB gene (W566R; 173410.0007). The mutation was identified by exome sequencing and confirmed by Sanger sequencing. The mutation occurred de novo in patient 1, and was not present in the unaffected mother and sister of patient 2.
Takenouchi et al. (2021) analyzed the serial neurovascular imaging studies of the first 2 patients reported with KOGS (Takenouchi et al., 2015), which showed progressive dilation of basilar and vertebral arteries starting in the teenage years and early twenties. The concurrent cardiovascular evaluations showed similar dilatory and tortuous changes in the coronary arteries. The authors recommended that in addition to counseling at the time of diagnosis, patients should receive optimal blood pressure control and systemic vascular screening starting in the teenage years.
In a 10-year-old boy with KOGS, Gawlinski et al. (2018) identified de novo heterozygosity for the previously reported P584R mutation (173410.0005) in the PDGFRB gene. The mutation was identified by trio whole-exome sequencing. The patient had several typical features of KOGS but also some progressive features not previously reported in this syndrome.
Gawlinski, P., Pelc, M., Ciara, E., Jhangiani, S., Jurkiewicz, E., Gambin, T., Rozdzynska-Swiatkowska, A., Dawidziuk, M., Coban-Akdemir, Z. H., Guilbride, D. L., Muzny, D., Lupski, J. R., Krajewska-Walasek, M. Phenotype expansion and development in Kosaki overgrowth syndrome. Clin. Genet. 93: 919-924, 2018. [PubMed: 29226947] [Full Text: https://doi.org/10.1111/cge.13192]
Minatogawa, M., Takenouchi, T., Tsuyusaki, Y., Iwasaki, F., Uenara, T., Kurosawa, K., Kosaki, K., Curry, C. J. Expansion of the phenotype of Kosaki overgrowth syndrome. Am. J. Med. Genet. 173A: 2422-2427, 2017. [PubMed: 28639748] [Full Text: https://doi.org/10.1002/ajmg.a.38310]
Takenouchi, T., Kodo, K., Yamazaki, F., Nakatomi, H., Kosaki, K. Progressive cerebral and coronary aneurysms in the original two patients with Kosaki overgrowth syndrome. Am. J. Med. Genet. 185: 999-1003, 2021. [PubMed: 33382209] [Full Text: https://doi.org/10.1002/ajmg.a.62027]
Takenouchi, T., Yamaguchi, Y., Tanikawa, A., Kosaki, R., Okano, H., Kosaki, K. Novel overgrowth syndrome phenotype due to recurrent de novo PDGFRB mutation. J. Pediat. 166: 483-486, 2015. [PubMed: 25454926] [Full Text: https://doi.org/10.1016/j.jpeds.2014.10.015]
Watanabe, K., Okada, E., Kosaki, K., Tsuji, T., Ishii, K., Nakamura, M., Chiba, K., Toyama, Y., Matsumoto, M. Surgical treatment for scoliosis in patients with Shprintzen-Goldberg syndrome. J. Pediat. Orthop. 31: 186-193, 2011. [PubMed: 21307714] [Full Text: https://doi.org/10.1097/BPO.0b013e3182093da5]